Ang II and Aldosterone Effects on Insulin Resistance in Cardiovascular Tissue

Summary

Principal Investigator: JAMES RUSSELL SOWERS
Abstract: DESCRIPTION (provided by applicant): Decreased insulin sensitivity is a cardinal feature of various pathological conditions such as type 2 diabetes and hypertension. Recent research has implicated a heightened renin-angiotensin-aldosterone system (RAAS) and associated enhanced oxidative stress in the pathogenesis and cardiovascular complications of insulin resistance in people with diabetes and hypertension. We posit that activation of serine (Ser) kinase signaling pathways, in conjunction with excess generation of reactive oxygen species (ROS), constitute one of the mechanisms whereby angiotensin II (Ang II) and aldosterone contribute to insulin resistance in cardiovascular tissue. In our preliminary investigation, as well as in work from other laboratories, the redox-sensitive Ser kinase Rho kinase (ROK), has surfaced as a potentially important mediator of Ang II and aldosterone induced insulin resistance. Research, primarily conducted in fat and skeletal muscle tissue, indicates that several Ser kinases, including ROK, may inhibit insulin metabolic signaling by inducing site specific Ser phosphorylation of the critical docking protein insulin receptor substrate-1 (IRS-1). Accordingly, we hypothesize that RAAS activation of redox sensitive ROK inhibits insulin mediated IRS- 1/PI3-K/Akt signaling by causing site directed IRS-1 Ser phosphorylation in cardiovascular tissue. A corollary to this hypothesis is that chronic exposure to excess RAAS activates ROS/ROK pathways leading to impairment of vasorelaxation, myocardial glucose utilization and diastolic relaxation because of ROK induced site-specific Ser phosphorylation of IRS-1. In our proposed research, we plan to use mass spectroscopy and other novel techniques to investigate site specific Ser and tyrosine (Tyr) phosphorylation of IRS-1 in relation to Ang II and aldosterone induced insulin resistance. The role of ROK in mediating insulin resistance will be investigated in primary cultured cells and in vivo/ex vivo studies in cardiovascular tissues of rodents with excess long-term exposure to Ang II and/or aldosterone, with and without Ang II and mineralocorticoid receptor blockade, and ROK inhibition. To address Specific Aim 1, we will employ siRNA for the two ROK isoforms as well as chemical inhibitors of ROS/ROK signaling in cells pretreated with Ang II, aldosterone, or both, before measuring metabolic and functional responses to insulin in primary cultured rat endothelial, vascular smooth muscle and cardiomyocyte cells. In Specific Aim 2, we will conduct both in vivo and ex vivo determination of the impact of chronic Ang II and/or aldosterone exposure on metabolic signaling through the insulin/IRS-1 pathway in heart, vasculature and skeletal muscle. We will utilize our state of the art rodent imaging center to conduct critical in vivo investigations, employ positron emission tomography (PET) scanning to evaluate insulin stimulated glucose uptake in the heart, and cine-magnetic resonance imaging to evaluate insulin sensitive cardiac diastolic relaxation. We will also employ direct visualization of skeletal muscle arterioles using video microscopy to evaluate insulin induced nitric oxide dependent vasodilation. Co-investigators include an imaging physicist, a vascular biologist and an expert in mass spectroscopy to evaluate site specific Ser and Tyr phosphorylation of the IRS-1 docking protein. Our proposed investigation should provide novel information on the mechanisms by which Ang II and/or aldosterone, acting collectively and individually, contribute to impaired insulin metabolic signaling and compromised cardiovascular function in conditions of insulin resistance such as hypertension and diabetes. This research should uncover new therapeutic strategies that can prevent excessive Ser phosphorylation of IRS-1 associated with a heightened RAAS in persons with hypertension and diabetes. Lay Summary Insulin is critical for normal cardiovascular function as well as for maintaining normal blood glucose levels. Tissue resistance to the normal metabolic actions of insulin is often present in persons with hypertension, and is a precursor for diabetes and cardiovascular disease. The fundamental mechanisms underlying insulin resistance in cardiovascular tissue, as well as skeletal muscle, are not well understood, and our proposed work is directed at elucidation of these mechanisms. A better understanding of factors involved in insulin resistance should enable development of therapeutic targets to help prevent diabetes and cardiovascular disease.
Funding Period: 2009-05-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. ncbi Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease
    Jun Ren
    Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
    J Mol Med (Berl) 88:993-1001. 2010
  2. pmc Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway
    Adam T Whaley-Connell
    Harry S Truman VA Medical Center, Columbia, MO, USA
    Am J Nephrol 35:90-100. 2012
  3. pmc Evidence-based hypertension treatment in patients with diabetes
    Mariana Garcia-Touza
    Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, MO 65212, USA
    J Clin Hypertens (Greenwich) 14:97-102. 2012
  4. pmc Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats
    Tadashi Sofue
    Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
    Am J Hypertens 25:604-11. 2012
  5. pmc Over-nutrition contributes to tubulointerstitial fibrosis by targeting nutrient-sensing kinases: Role for the mTOR/S6K pathway
    Ravi Nistala
    University of Missouri School of Medicine University of Missouri Columbia, MO USA Department of Internal Medicine University of Missouri Columbia, MO USA Division of Nephrology and Hypertension University of Missouri Columbia, MO USA Dialysis Clinics, Inc Columbia, MO USA
    Cell Cycle 11:831-2. 2012
  6. pmc Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction
    Vincent G Demarco
    Diabetes and Cardiovascular Center, University of Missouri, Columbia, USA
    Am J Physiol Heart Circ Physiol 302:H1667-82. 2012
  7. pmc Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat
    Lixin Ma
    Department of Radiology, University of Missouri School of Medicine, Columbia, USA
    Am J Physiol Heart Circ Physiol 302:H2341-51. 2012
  8. pmc Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat
    Adam Whaley-Connell
    Harry S Truman VA Medical Center, University of Missouri Columbia School of Medicine, Columbia, MO 65211, USA
    Regul Pept 176:36-44. 2012
  9. pmc Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats
    Jasmina Varagic
    Hypertension and Vascular Research Center, Wake Forest University, Winston Salem, North Carolina 27157, USA
    J Hypertens 30:1766-74. 2012
  10. pmc Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation
    Jeong A Kim
    Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Universityof Alabama at Birmingham Comprehensive Diabetes Center, AL 35294, USA
    Am J Physiol Endocrinol Metab 302:E201-8. 2012

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. Interactions of the RAAS and a Western Diet on Insulin Metabolic Actions
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
  3. Ang II and Overnutrition and Insulin resistance in Cardiovascular Tissue
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
  4. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
  5. JHU-UMD Diabetes Research Center
    Fredric E Wondisford; Fiscal Year: 2013
  6. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  7. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  8. Effects of insulin on the microvasculature
    EUGENE JOSEPH BARRETT; Fiscal Year: 2013
  9. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013

Detail Information

Publications114 found, 100 shown here

  1. ncbi Mitochondrial biogenesis in the metabolic syndrome and cardiovascular disease
    Jun Ren
    Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA
    J Mol Med (Berl) 88:993-1001. 2010
    ..This review explores mechanisms of mitochondrial dysfunction with a focus on impaired oxidative phosphorylation and mitochondrial biogenesis in the pathophysiology of metabolic heart disease...
  2. pmc Mineralocorticoid receptor-dependent proximal tubule injury is mediated by a redox-sensitive mTOR/S6K1 pathway
    Adam T Whaley-Connell
    Harry S Truman VA Medical Center, Columbia, MO, USA
    Am J Nephrol 35:90-100. 2012
    ..Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics...
  3. pmc Evidence-based hypertension treatment in patients with diabetes
    Mariana Garcia-Touza
    Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri, Columbia, MO 65212, USA
    J Clin Hypertens (Greenwich) 14:97-102. 2012
    ..We would posit that a BP goal of 135/85 mm Hg may be a reasonable compromise when viewing the impact of BP reduction on composite stroke and coronary artery disease in extant trials...
  4. pmc Early treatment with olmesartan prevents juxtamedullary glomerular podocyte injury and the onset of microalbuminuria in type 2 diabetic rats
    Tadashi Sofue
    Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
    Am J Hypertens 25:604-11. 2012
    ....
  5. pmc Over-nutrition contributes to tubulointerstitial fibrosis by targeting nutrient-sensing kinases: Role for the mTOR/S6K pathway
    Ravi Nistala
    University of Missouri School of Medicine University of Missouri Columbia, MO USA Department of Internal Medicine University of Missouri Columbia, MO USA Division of Nephrology and Hypertension University of Missouri Columbia, MO USA Dialysis Clinics, Inc Columbia, MO USA
    Cell Cycle 11:831-2. 2012
    ..Comment on: Whaley-Connell A, et al. Am J Nephrol 2011; 34:115-25...
  6. pmc Overweight female rats selectively breed for low aerobic capacity exhibit increased myocardial fibrosis and diastolic dysfunction
    Vincent G Demarco
    Diabetes and Cardiovascular Center, University of Missouri, Columbia, USA
    Am J Physiol Heart Circ Physiol 302:H1667-82. 2012
    ....
  7. pmc Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat
    Lixin Ma
    Department of Radiology, University of Missouri School of Medicine, Columbia, USA
    Am J Physiol Heart Circ Physiol 302:H2341-51. 2012
    ..These results support that targeting NO with nebivolol treatment improves diastolic dysfunction through reducing myocardial oxidative stress by enhancing 5'-AMP-activated protein kinase and Akt activation of NO biosynthesis...
  8. pmc Combination of direct renin inhibition with angiotensin type 1 receptor blockade improves aldosterone but does not improve kidney injury in the transgenic Ren2 rat
    Adam Whaley-Connell
    Harry S Truman VA Medical Center, University of Missouri Columbia School of Medicine, Columbia, MO 65211, USA
    Regul Pept 176:36-44. 2012
    ..Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels...
  9. pmc Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats
    Jasmina Varagic
    Hypertension and Vascular Research Center, Wake Forest University, Winston Salem, North Carolina 27157, USA
    J Hypertens 30:1766-74. 2012
    ..This study evaluated the hypothesis that nebivolol reduces salt-induced cardiac remodeling and dysfunction in spontaneous hypertensive rats (SHRs) by suppressing cardiac RAS and oxidative stress...
  10. pmc Activation of mTOR/p70S6 kinase by ANG II inhibits insulin-stimulated endothelial nitric oxide synthase and vasodilation
    Jeong A Kim
    Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Universityof Alabama at Birmingham Comprehensive Diabetes Center, AL 35294, USA
    Am J Physiol Endocrinol Metab 302:E201-8. 2012
    ..This ANG II-mediated impairment of vascular actions of insulin may help explain the role of ANG II as a link between insulin resistance and hypertension...
  11. pmc Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat
    Vincent G Demarco
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Am J Physiol Heart Circ Physiol 300:H181-90. 2011
    ....
  12. pmc Pericytopathy: oxidative stress and impaired cellular longevity in the pancreas and skeletal muscle in metabolic syndrome and type 2 diabetes
    Melvin R Hayden
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO, USA
    Oxid Med Cell Longev 3:290-303. 2010
    ..In conclusion, we have provided a review of current knowledge regarding the pericyte and novel ultrastructural findings regarding its role in metabolic syndrome and T2DM...
  13. pmc Nebivolol attenuates redox-sensitive glomerular and tubular mediated proteinuria in obese rats
    Javad Habibi
    Diabetes and Cardiovascular Center, the University of Missouri ColumbiaSchool of Medicine, Columbia, Missouri 65211, USA
    Endocrinology 152:659-68. 2011
    ....
  14. pmc Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression
    Javad Habibi
    Department of Internal Medicine, University of Missouri, Columbia, 65212, USA
    Am J Physiol Heart Circ Physiol 300:H1484-91. 2011
    ..These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure...
  15. pmc Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat
    Camila Manrique
    Diabetes Cardiovascular Center of Excellence, University of Missouri Columbia School of Medicine, Columbia, MO 65212, USA
    Metabolism 60:1757-66. 2011
    ....
  16. pmc Bariatric surgery reduces visceral adipose inflammation and improves endothelial function in type 2 diabetic mice
    Hanrui Zhang
    Department of Internal Medicine, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA
    Arterioscler Thromb Vasc Biol 31:2063-9. 2011
    ..We hypothesize that bariatric surgery ameliorates interferon-γ-mediated adipose tissue inflammation/oxidative stress and improves endothelial function in type 2 diabetic mice...
  17. pmc Angiotensin II activation of mTOR results in tubulointerstitial fibrosis through loss of N-cadherin
    Adam Whaley-Connell
    Harry S Truman VA Medical Center, and the University of Missouri Columbia School of Medicine, USA whaleyconnella health missouri edu
    Am J Nephrol 34:115-25. 2011
    ..Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis...
  18. pmc Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities
    Lakshmi Pulakat
    University of Missouri School of Medicine, Department of Internal Medicine, Columbia, Missouri 65212, USA
    Am J Physiol Regul Integr Comp Physiol 301:R885-95. 2011
    ..We posit that such a lack of activation of the mTOR↔AT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes...
  19. pmc Sex differences in baroreflex sensitivity, heart rate variability, and end organ damage in the TGR(mRen2)27 rat
    Megan S Johnson
    Department of Biological Sciences, University of Missouri, Columbia, Missouri, USA
    Am J Physiol Heart Circ Physiol 301:H1540-50. 2011
    ..These data demonstrated relative protection in females from autonomic dysfunction and end-organ damage associated with elevated blood pressure in the Ren2 model of hypertension...
  20. pmc Interferon-gamma induced adipose tissue inflammation is linked to endothelial dysfunction in type 2 diabetic mice
    Hanrui Zhang
    Department of Internal Medicine, Dalton Cardiovascular Research Center, University of Missouri Columbia, Columbia, MO 65211, USA
    Basic Res Cardiol 106:1135-45. 2011
    ..These findings suggest IFNγ has a key role in the regulation of visceral adipose tissue inflammatory response and endothelial dysfunction in type 2 diabetes...
  21. ncbi Hypertension in obesity
    L Romayne Kurukulasuriya
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, MO 65212, USA
    Med Clin North Am 95:903-17. 2011
    ....
  22. pmc Insulin resistance and heart failure: molecular mechanisms
    Annayya R Aroor
    Department of Internal Medicine, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65212, USA
    Heart Fail Clin 8:609-17. 2012
    ..Understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance...
  23. pmc Obesity-related alterations in cardiac lipid profile and nondipping blood pressure pattern during transition to diastolic dysfunction in male db/db mice
    Vincent G Demarco
    Departments of Internal Medicine, University of Missouri Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA
    Endocrinology 154:159-71. 2013
    ..In conclusion, a distinct pattern of myocardial lipid remodeling, accompanied by oxidative stress, is associated with the onset of diastolic dysfunction in obese, insulin-resistant db/db mice...
  24. pmc Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance
    Annayya R Aroor
    Division of Endocrinology, Diabetes and Metabolism, Diabetes Cardiovascular Center, University of Missouri, Columbia, MO, USA Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA
    Metabolism 62:1543-52. 2013
    ..g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance...
  25. pmc Salt loading exacerbates diastolic dysfunction and cardiac remodeling in young female Ren2 rats
    Adam T Whaley-Connell
    Research Service Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO 65212, USA University of Missouri School of Medicine, Departments of Internal Medicine, Divisions of Nephrology and Hypertension, Columbia, MO, USA University of Missouri School of Medicine, Departments of Internal Medicine, Division of Endocrinology and Metabolism, Columbia, MO, USA University of Missouri School of Medicine, Diabetes and Cardiovascular Center, Columbia, MO, USA Electronic address
    Metabolism 62:1761-71. 2013
    ....
  26. pmc Diabetic kidney disease and the cardiorenal syndrome: old disease, new perspectives
    Ankur Jindal
    Hospital Medicine, Department of Internal Medicine, University of Missouri, One Hospital Drive, Columbia, MO 65212, USA Diabetes and Cardiovascular Research Center, University of Missouri, One Hospital Drive, Columbia, MO 65212, USA
    Endocrinol Metab Clin North Am 42:789-808. 2013
    ..The importance of glycemic and blood pressure control in patients with diabetes and chronic kidney disease, and the use of oral hypoglycemic agents and antihypertensive agents in this patient cohort, are also discussed. ..
  27. pmc Combining metformin and aerobic exercise training in the treatment of type 2 diabetes and NAFLD in OLETF rats
    Melissa A Linden
    Research Service, Harry S Truman Memorial Veterans Affairs Hospital
    Am J Physiol Endocrinol Metab 306:E300-10. 2014
    ..Combining therapies offered little additional benefit beyond exercise alone, and findings suggest that metformin potentially impairs exercise-induced hepatic mitochondrial adaptations. ..
  28. pmc Type 2 diabetes mellitus and hypertension: an update
    Guido Lastra
    Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Missouri Columbia School of Medicine, D109 Diabetes Center HSC, One Hospital Drive, Columbia, MO 65212, USA Diabetes and Cardiovascular Research Center, University of Missouri, One Hospital Drive, Columbia, MO 65212, USA Harry S Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA
    Endocrinol Metab Clin North Am 43:103-22. 2014
    ..Emerging therapies for resistant hypertension as often exists in patients with diabetes, include renal denervation and carotid body denervation. ..
  29. pmc New insights into insulin action and resistance in the vasculature
    Camila Manrique
    Division of Endocrinology, Department of Internal Medicine, University of Missouri, Columbia, Missouri Harry S Truman Veteran s Hospital, Columbia, Missouri
    Ann N Y Acad Sci 1311:138-50. 2014
    ..This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation. ..
  30. pmc Prevention of obesity-induced renal injury in male mice by DPP4 inhibition
    Ravi Nistala
    Divisions of Nephrology and Hypertension R N, A M, A W C and Endocrinology and Metabolism J H, G L, C M, A R A, M R H, M G, A W C, J R S, Departments of Internal Medicine R N, J H, G L, C M, A R A, M R H, M G, A M, A W C, J R S and Medical Pharmacology and Physiology J R S, Diabetes and Cardiovascular Center R N, J H, G L, C M, A R A, M R H, M G, A M, M J, A W C, J R S, University of Washington
    Endocrinology 155:2266-76. 2014
    ....
  31. ncbi The pathophysiology of hypertension in patients with obesity
    Vincent G Demarco
    Internal Medicine, University of Missouri, Columbia School of Medicine, One Hospital Drive, Columbia, MO 65212, USA
    Nat Rev Endocrinol 10:364-76. 2014
    ..In this Review we discuss the relationship between obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might be used in a clinical setting. ..
  32. ncbi Obesity and insulin resistance induce early development of diastolic dysfunction in young female mice fed a Western diet
    Camila Manrique
    MD, Professor of Medicine and Medical Pharmacology and Physiology, University of Missouri, D109 Diabetes Center Health Sciences Center, One Hospital Drive, Columbia, Missouri 65212
    Endocrinology 154:3632-42. 2013
    ..These data are consistent with the notion that higher aldosterone levels, in concert with insulin resistance, may promote myocardial stiffness and diastolic dysfunction in response to overnutrition in females. ..
  33. pmc Molecular and metabolic mechanisms of cardiac dysfunction in diabetes
    Chirag H Mandavia
    University of Missouri School of Medicine, Department of Internal Medicine, Columbia, MO, USA
    Life Sci 92:601-8. 2013
    ..Elucidation of these mechanisms should provide a better understanding of the various cardiac abnormalities associated with diastolic dysfunction and its progression to systolic dysfunction and heart failure...
  34. pmc Role of insulin resistance in endothelial dysfunction
    Ranganath Muniyappa
    Clinical Endocrine Section, Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
    Rev Endocr Metab Disord 14:5-12. 2013
    ....
  35. pmc Therapy of obese patients with cardiovascular disease
    Ankur Jindal
    University of Missouri Columbia, School of Medicine, United States
    Curr Opin Pharmacol 13:200-4. 2013
    ..We summarize the treatment options for obesity and the efficacy of these options in ameliorating cardiovascular risk factors. We also focus on the recently approved antiobesity drugs. ..
  36. pmc Mineralocorticoid receptor-mediated vascular insulin resistance: an early contributor to diabetes-related vascular disease?
    Shawn B Bender
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA
    Diabetes 62:313-9. 2013
    ....
  37. pmc Renin inhibition and AT(1)R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling
    Adam Whaley-Connell
    Research Service, Harry S Truman Memorial Veterans Hospital, 800 Hospital Drive, Columbia, MO 65201, USA
    Metabolism 62:861-72. 2013
    ....
  38. pmc Angiotensin type 1 receptor resistance to blockade in the opossum proximal tubule cell due to variations in the binding pocket
    Ravi Nistala
    Division of Nephrology, Department of Internal Medicine, University of Missouri Columbia, Columbia, MO 65212, USA
    Am J Physiol Renal Physiol 304:F1105-13. 2013
    ..These observations highlight the potential utility of evaluating AT(1)R polymorphisms within the ARB-binding pocket in various hypertensive populations...
  39. ncbi Obesity and heart failure as a mediator of the cerebrorenal interaction
    Ankur Jindal
    Department of Internal Medicine, University of Missouri, Columbia, MO, USA
    Contrib Nephrol 179:15-23. 2013
    ..g. stroke). Whether the relationship between obesity, heart disease/failure and risk for chronic kidney disease and stroke is direct or a confluence of risk factors is poorly understood...
  40. pmc Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats
    Annayya R Aroor
    Department of Internal Medicine, University of Missouri School of Medicine, and Diabetes and Cardiovascular Center, Columbia, MO 65212, USA
    Endocrinology 154:2501-13. 2013
    ....
  41. pmc Fructose and uric acid: is there a role in endothelial function?
    Guanghong Jia
    Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA
    Curr Hypertens Rep 16:434. 2014
    ..A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies. ..
  42. pmc Reactive oxygen species signaling in vascular smooth muscle cells
    Roza E Clempus
    Department of Medicine, Division of Cardiology, Emory University, 319 WMB, 1639 Pierce Dr Atlanta, GA 30322, USA
    Cardiovasc Res 71:216-25. 2006
    ..Therefore, it becomes critical to understand the different roles ROS play in the physiology and pathophysiology of VSMCs...
  43. ncbi Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling
    Sameer Stas
    Division of Endocrinology, University of Missouri School of Medicine, Columbia, Missouri 65212, USA
    Endocrinology 148:3773-80. 2007
    ....
  44. ncbi Isletopathy in Type 2 diabetes mellitus: implications of islet RAS, islet fibrosis, islet amyloid, remodeling, and oxidative stress
    Melvin R Hayden
    University of Missouri School of Medicine Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Research Group, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Antioxid Redox Signal 9:891-910. 2007
    ....
  45. ncbi Longitudinal ultrastructure study of islet amyloid in the HIP rat model of type 2 diabetes mellitus
    Melvin R Hayden
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Exp Biol Med (Maywood) 232:772-9. 2007
    ....
  46. ncbi NADPH oxidase contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat
    Yongzhong Wei
    University of Missouri Columbia, Harry S Truman VA Medical Center, Columbia, MO, USA
    Hypertension 50:384-91. 2007
    ..Collectively, these data suggest that increased angiotensin type 1 receptor/NADPH oxidase activation/reactive oxygen species contribute to vascular insulin resistance, endothelial dysfunction, apoptosis, and inflammation...
  47. ncbi Myocardial myocyte remodeling and fibrosis in the cardiometabolic syndrome
    Melvin R Hayden
    Department of Internal Medicine University of Missouri School of Medicine, Columbia, MO 65212, USA
    J Cardiometab Syndr 1:326-33. 2006
    ..This review and the preliminary observational findings may provide the clinician and researcher a better understanding of remodeling changes in the myocardium and ultimately foster earlier recognition and therapeutic interventions...
  48. ncbi Insulin resistance, oxidative stress, and podocyte injury: role of rosuvastatin modulation of filtration barrier injury
    Adam Whaley-Connell
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, MO 65212, USA
    Am J Nephrol 28:67-75. 2008
    ..The glomerular filtration barrier is emerging as a critical determinant of albumin filtration. We investigated the effects of insulin resistance and rosuvastatin or placebo on the glomerular filtration barrier...
  49. ncbi Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell
    Melvin R Hayden
    Department of Internal Medicine, University of Missouri School of Medicine, D109 HSC Diabetes Center, Columbia, MO 65212, USA
    JOP 8:725-38. 2007
    ..We have integrated the role of the islet renin-angiotensin system (RAS) in the pathogenesis of early islet fibrosis utilizing the transgenic (mRen2)27 rodent model of hypertension and tissue RAS overexpression...
  50. ncbi Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase
    Yongzhong Wei
    Diabetes Research Program, Department of Medicine, University of Arizona, Tucson, AZ 85724, USA
    Am J Physiol Endocrinol Metab 294:E345-51. 2008
    ..These findings suggest that NF-kappaB plays an important role in ANG II/ROS-induced skeletal muscle insulin resistance...
  51. pmc Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment
    Adam Whaley-Connell
    University of Missouri Columbia School of Medicine, Department of Internal Medicine, Division of Nephrology, MA436, DC043 0, One Hospital Dr, Columbia, MO 65212, USA
    Hypertension 51:474-80. 2008
    ....
  52. ncbi Aldosterone and hypertension in the cardiometabolic syndrome
    Sameer Stas
    J Clin Hypertens (Greenwich) 10:94-6. 2008
  53. pmc Role of mitochondrial dysfunction in insulin resistance
    Jeong A Kim
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, Missouri, USA
    Circ Res 102:401-14. 2008
    ..In this review, we discuss mechanisms of mitochondrial dysfunction related to the pathophysiology of insulin resistance in classic insulin-responsive tissue, as well as cardiovascular tissue...
  54. ncbi The cardiometabolic syndrome and liver disease
    James R Sowers
    J Cardiometab Syndr 3:5-6. 2008
  55. ncbi Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat
    Adam Whaley-Connell
    University of Missouri Columbia School of Medicine, Division of Nephrology, MA436, DC043 0, One Hospital Dr, Columbia, MO 65212, USA
    Am J Physiol Endocrinol Metab 293:E355-63. 2007
    ..05). Collectively, these data suggest cardiac oxidative stress-induced structural and functional changes are driven, in part, by AT(1)R-mediated increases in NADPH oxidase activity...
  56. ncbi Alcohol consumption and blood pressure in the adult US population: assessment of gender-related effects
    Samy I McFarlane
    Division of Endocrinology Biostatistics, SUNY Downstate Medical Center Kings County Hospital, Brooklyn, New York 11203, USA
    J Hypertens 25:965-70. 2007
    ..Our objective was to assess the gender-related effects of alcohol consumption on blood pressure (BP) in a representative sample of the adult US population...
  57. ncbi Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat
    Adam T Whaley-Connell
    Department of Internal Medicine, University of Missouri School of Medicine, 1 Hospital Dr, MA410 Medical Science Bldg, Columbia, MO 65212, USA
    Am J Physiol Renal Physiol 291:F1308-14. 2006
    ..Thus reductions in blood pressure, albuminuria, and tissue oxidative stress with AT1R blockade were associated with improved indexes of glomerular filtration barrier integrity and renal RAS in Ren2 rats...
  58. ncbi Modulation of vascular smooth muscle signaling by reactive oxygen species
    Alicia N Lyle
    Department of Medicine, Division of Cardiology, Emory University, Atlanta, Georgia, USA
    Physiology (Bethesda) 21:269-80. 2006
    ..Identifying the precise intracellular targets of ROS enhances understanding of their role in cardiovascular physiology and pathophysiology...
  59. ncbi Anemia and cardiovascular disease in diabetic nephropathy
    Samy I McFarlane
    Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, State University of New York Health Science Center at Brooklyn, Kings County Hospital Center, 450 Clarkson Avenue, Box 50, Brooklyn, NY 11203 2098, USA
    Curr Diab Rep 6:213-8. 2006
    ....
  60. ncbi Metabolic safety of antihypertensive drugs: myth versus reality
    Sameer Stas
    University of Missouri Medical Center, Department of Internal Medicine, Health Sciences Center, Columbia, MO 652212, USA
    Curr Hypertens Rep 8:403-8. 2006
    ....
  61. ncbi Angiotensin II-induced NADPH oxidase activation impairs insulin signaling in skeletal muscle cells
    Yongzhong Wei
    Department of Internal Medicine, University of Missouri Columbia 65212, USA
    J Biol Chem 281:35137-46. 2006
    ..These results suggest a pivotal role for NADPH oxidase activation and ROS generation in Ang II-induced inhibition of insulin signaling in skeletal muscle cells...
  62. pmc NADPH oxidases: new regulators of old functions
    Kathy K Griendling
    Antioxid Redox Signal 8:1443-5. 2006
  63. ncbi The metabolic syndrome: role of skeletal muscle metabolism
    Craig S Stump
    MU Diabetes and Cardiovascular Research Center, Columbia, Missouri, USA
    Ann Med 38:389-402. 2006
    ..Strategies will include adequate physical activity and maintaining a healthy weight, but may also require specific pharmacologic interventions...
  64. ncbi Proximal tubule microvilli remodeling and albuminuria in the Ren2 transgenic rat
    Melvin R Hayden
    Department of Internal Medicine, University of Missouri, Columbia, USA
    Am J Physiol Renal Physiol 292:F861-7. 2007
    ..These data indicate that PTC structural damage in the Ren2 rat is related to the oxidative stress response to ANG II and/or albuminuria...
  65. pmc Nox4 is required for maintenance of the differentiated vascular smooth muscle cell phenotype
    Roza E Clempus
    Emory University, Division of Cardiology, 1639 Pierce Dr, Atlanta, GA 30322, USA
    Arterioscler Thromb Vasc Biol 27:42-8. 2007
    ..Reactive oxygen species (ROS) have been implicated in VSMC differentiation, but the responsible sources are unknown. In this study, we investigated the role of Nox1 and Nox4-derived ROS in this process...
  66. ncbi Albumin activation of NAD(P)H oxidase activity is mediated via Rac1 in proximal tubule cells
    Adam T Whaley-Connell
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Am J Nephrol 27:15-23. 2007
    ..Thus in states of albumin overload, Rac1 activation could lead to NOX activation and ROS formation in the PTC. Furthermore, accumulating evidence supports that HMG-CoA reductase inhibition may reduce oxidative stress and albuminuria...
  67. pmc Measurement of reactive oxygen species in cardiovascular studies
    Sergey Dikalov
    Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA 30322, USA
    Hypertension 49:717-27. 2007
  68. ncbi Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, decreases cardiac oxidative stress and remodeling in Ren2 transgenic rats
    Javad Habibi
    University of Missouri School of Medicine, Columbia, Missouri 65212, USA
    Endocrinology 148:2181-8. 2007
    ..05). These results suggest that in vivo statin treatment through its direct actions on the heart reduces oxidative stress and remodeling including ventricular mass regression in the Ang-II-dependent Ren2 model...
  69. ncbi Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat
    Vincent G Demarco
    Department of Child Health, University of Missouri School of Medicine, Columbia, Missouri 65210, USA
    Am J Physiol Heart Circ Physiol 294:H2659-68. 2008
    ..05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling...
  70. pmc Low-dose spironolactone reduces reactive oxygen species generation and improves insulin-stimulated glucose transport in skeletal muscle in the TG(mRen2)27 rat
    Guido Lastra
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Am J Physiol Endocrinol Metab 295:E110-6. 2008
    ..05). Our findings suggest that aldosterone contributes to insulin resistance in the transgenic Ren2, in part, by increasing NADPH oxidase activity in skeletal muscle tissue...
  71. pmc Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic Ren2 rat
    Adam Whaley-Connell
    The University of Missouri School of Medicine, Department of Medicine, Columbia, Missouri, USA
    Am J Physiol Endocrinol Metab 295:E103-9. 2008
    ..Collectively, these data suggest that both reduce changes driven, in part, by Ang II-mediated increases in NADPH oxidase and, in part, increases in blood pressure...
  72. pmc The renin angiotensin aldosterone system in hypertension: roles of insulin resistance and oxidative stress
    Camila Manrique
    Department of Internal Medicine, Diabetes and Cardiovascular Center, University of Missouri, Columbia, MO 65212, USA
    Med Clin North Am 93:569-82. 2009
    ....
  73. pmc Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension
    James R Sowers
    University of Missouri, Columbia, Missouri, USA
    Ann Intern Med 150:776-83. 2009
    ....
  74. pmc Nebivolol reduces proteinuria and renal NADPH oxidase-generated reactive oxygen species in the transgenic Ren2 rat
    Adam Whaley-Connell
    The University of Missouri School of Medicine, Department of Internal Medicine, Division of Nephrology and Hypertension CE417, DC043 0, Five, Hospital Dr, Columbia, MO 65212, USA
    Am J Nephrol 30:354-60. 2009
    ..Thereby, we hypothesized that in vivo nebivolol therapy in a rodent model of activated RAAS would attenuate glomerular damage and proteinuria through its actions to reduce NADPH oxidase activity/ROS and increase bioavailable NO...
  75. ncbi Utility of aspirin therapy in patients with the cardiometabolic syndrome and diabetes
    Michael Gardner
    Diabetes and Cardiovascular Center, University of Missouri School of Medicine and Truman VA Hospital, Columbia, MO 65212, USA
    J Cardiometab Syndr 4:96-101. 2009
    ..They also explore, in addition to aspirin's effects on platelet aggregation, some of the mechanisms by which aspirin may favorably alter the course of atherosclerosis, effects on endothelial function, and glycemia...
  76. pmc Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat
    Vincent G Demarco
    Department of Child Health, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Am J Physiol Heart Circ Physiol 297:H1128-39. 2009
    ..These data suggest that statins may be a clinically viable adjunct treatment of PAH through reducing peroxynitrite formation...
  77. pmc Comparative effect of direct renin inhibition and AT1R blockade on glomerular filtration barrier injury in the transgenic Ren2 rat
    Adam Whaley-Connell
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, Missouri 65212, USA
    Am J Physiol Renal Physiol 298:F655-61. 2010
    ..Our results highlight both the importance of pressor-related reductions on podocyte integrity and albuminuria as well as RAS-mediated oxidant stress largely comparable between ARB and renin inhibition treatment...
  78. pmc Nebivolol attenuates maladaptive proximal tubule remodeling in transgenic rats
    Melvin R Hayden
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, USA
    Am J Nephrol 31:262-72. 2010
    ..Accordingly, we hypothesized that nebivolol therapy would attenuate PTC damage and tubulointerstitial fibrosis...
  79. pmc Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat
    Xinli Zhou
    Department of Internal Medicine, University of Missouri, 1 Hospital Drive, Columbia, MO 65212, USA
    Hypertension 55:880-8. 2010
    ....
  80. pmc Aldosterone: role in the cardiometabolic syndrome and resistant hypertension
    Adam Whaley-Connell
    Department of Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, MO 65212, USA
    Prog Cardiovasc Dis 52:401-9. 2010
    ..In summary, aldosterone excess exerts detrimental metabolic effects that contribute to the development of the CMS and resistant hypertension as well as CVD and CKD...
  81. pmc Treating hypertension while protecting the vulnerable islet in the cardiometabolic syndrome
    Melvin R Hayden
    Departments of Internal Medicine, Endocrinology Diabetes and Metabolism, and Diabetes and Cardiovascular Disease Research Center, School of Medicine, University of Missouri Columbia, Health Sciences Center, Columbia, Missouri, USA
    J Am Soc Hypertens 2:239-66. 2008
    ..Various classes of antihypertensive drugs are reviewed, especially their roles in delaying or preventing damage to the vulnerable pancreatic islet, and thus delaying the development of type 2 diabetes mellitus...
  82. pmc Mineralocorticoid receptor antagonism attenuates glomerular filtration barrier remodeling in the transgenic Ren2 rat
    Adam Whaley-Connell
    Internal Medicine, University of Missouri Columbia School of Medicine, Columbia, MO 65212, USA
    Am J Physiol Renal Physiol 296:F1013-22. 2009
    ..Thus, in this model of RAAS activation, MR antagonism attenuates glomerular/podocyte remodeling and albuminuria, in part through reductions in redox-mediated impairment of insulin metabolic signaling...
  83. pmc Oxidative stress-mediated mitochondrial dysfunction contributes to angiotensin II-induced nonalcoholic fatty liver disease in transgenic Ren2 rats
    Yongzhong Wei
    Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO 65212, USA
    Am J Pathol 174:1329-37. 2009
    ..These results document that ANG II induces mitochondrial oxidative damage and impairs mitochondrial beta-oxidation, contributing to liver steatosis...

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Interactions of the RAAS and a Western Diet on Insulin Metabolic Actions
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
    ..tyrosine (p) and the resultant downstream IRS-1/PI3-K/Akt signaling. ..
  3. Ang II and Overnutrition and Insulin resistance in Cardiovascular Tissue
    JAMES RUSSELL SOWERS; Fiscal Year: 2013
    ..A better understanding of factors involved in insulin resistance should help in the development of therapeutic targets to help prevent diabetes and cardiovascular disease. ..
  4. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  5. JHU-UMD Diabetes Research Center
    Fredric E Wondisford; Fiscal Year: 2013
    ..The Enrichment Program will facilitate the interaction within and between Johns Hopkins University and the University of Maryland. ..
  6. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  7. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  8. Effects of insulin on the microvasculature
    EUGENE JOSEPH BARRETT; Fiscal Year: 2013
    ....
  9. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  10. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  11. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..