Intermittent hypoxia, adiponectin, and insulin resistance in cardiovascular risk

Summary

Principal Investigator: NARASIMHAM LAXMI PARINANDI
Abstract: DESCRIPTION (provided by applicant): Cyclic intermittent hypoxia (IH) is emerging as an important factor in the development of insulin resistance and cardiovascular diseases in patients with obstructive sleep apnea (OSA). OSA is very common in congestive heart failure (CHF) occurring in up to a third of patients. Insulin resistance has also been linked to the development of cardiac dysfunction. Treatment of OSA with continuous positive airway pressure (CPAP) alleviates the IH during sleep, increases insulin sensitivity, as well as improves cardiac function, suggesting that IH is a crucial factor affecting myocardial function. The mechanisms by which IH is responsible for insulin resistance and associated cardiovascular diseases and myocardial dysfunctions are unclear. Adipose tissue synthesizes and secretes a wide variety of bioactive peptides which are collectively called "adipocytokines". Adiponectin (Ad), an adipoctyokine that is exclusively synthesized in white adipose tissue, has received considerable attention in recent years because of its potent physiological effects and pleiotropic actions which include its antidiabetic, antiatherogenic, and anti-inflammatory effects. Total circulating Ad levels have been shown to be lower in insulin-resistant individuals. Whether cyclic IH (similar to that encountered during the IH associated with OSA in humans) decreases Ad expression and secretion in adipocytes is not known. Therefore, in Specific Aim 1, we will examine whether IH alters Ad secretion in adipocytes resulting in increased insulin resistance in these cells. Ad protects against the development of systolic dysfunction following myocardial infarction. Ad deficiency leads to progressive cardiac remodeling in pressure overloaded condition and it also prevents cellular hypertrophy in cultured myocytes. It is not known whether the insulin resistance induced by IH contributes to myocardial dysfunction. Therefore, in Specific Aim 2, we will establish that adiponectin plays an important role in the modulation of insulin resistance and associated myocardial dysfunction induced by intermittent hypoxia in vivo, in animal models. Since insulin resistance is a risk factor for left ventricular systolic and diastolic function, and also our preliminary data show that treatment of IH in OSA increases the biologically active high-molecular-weight form of Ad, Specific Aim 3 of this proposal will involve translational research to examine the effects of CPAP treatment in human patients with OSA and heart failure, on insulin resistance and Ad levels, and associate these with changes in cardiac structure and function using cardiac magnetic resonance imaging. To carry out this proposal, we have assembled a team consisting of clinicians, basic scientist, and a leading authority on Ad biology. These collaborative efforts among clinician scientists and basic scientists, in a supportive environment at the Dorothy M. Davis Heart &Lung Institute of the Ohio State University College of Medicine, allow us to perform these experiments from cells and animal models to human subjects. PUBLIC HEALTH RELEVANCE: Intermittent hypoxia associated with obstructive sleep apnea is a very common problem that is an important risk factor for cardiovascular disease. Knowledge of the mechanisms of how adiponectin protects against intermittent hypoxia-induced insulin resistance and associated myocardial dysfunction, may provide novel treatment strategies for patients with sleep apnea and cardiovascular disease.
Funding Period: 2010-01-04 - 2014-11-30
more information: NIH RePORT

Top Publications

  1. pmc Pulmonary fibrosis inducer, bleomycin, causes redox-sensitive activation of phospholipase D and cytotoxicity through formation of bioactive lipid signal mediator, phosphatidic acid, in lung microvascular endothelial cells
    Rishi B Patel
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, 43210, USA
    Int J Toxicol 30:69-90. 2011
  2. pmc Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses
    Taryn G Aubrecht
    Department of Neuroscience and Institute of Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
    Am J Physiol Regul Integr Comp Physiol 305:R78-86. 2013
  3. pmc Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes
    Imran H Iftikhar
    Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of South Carolina, Columbia, SC, USA
    Ann Am Thorac Soc 10:115-20. 2013
  4. pmc Agreement in the scoring of respiratory events and sleep among international sleep centers
    Ulysses J Magalang
    Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
    Sleep 36:591-6. 2013
  5. pmc Effect of oral appliances on blood pressure in obstructive sleep apnea: a systematic review and meta-analysis
    Imran H Iftikhar
    University of South Carolina, School of Medicine, Columbia, SC, USA
    J Clin Sleep Med 9:165-74. 2013
  6. ncbi Choice of cyclodextrin for cellular cholesterol depletion for vascular endothelial cell lipid raft studies: cell membrane alterations, cytoskeletal reorganization and cytotoxicity
    Adam H Hinzey
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
    Indian J Biochem Biophys 49:329-41. 2012
  7. pmc Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction
    Kai Sun
    Touchstone Diabetes Center, Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Mol Cell Biol 33:904-17. 2013
  8. pmc Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N'-bis-2-mercap
    Rishi B Patel
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA
    Toxicol Mech Methods 22:383-96. 2012
  9. pmc Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease
    Smitha Malireddy
    Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
    Antioxid Redox Signal 17:327-39. 2012
  10. pmc Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium
    Jessica Rennolds
    Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210, United States
    Biochem Biophys Res Commun 417:256-61. 2012

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013

Detail Information

Publications14

  1. pmc Pulmonary fibrosis inducer, bleomycin, causes redox-sensitive activation of phospholipase D and cytotoxicity through formation of bioactive lipid signal mediator, phosphatidic acid, in lung microvascular endothelial cells
    Rishi B Patel
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, 43210, USA
    Int J Toxicol 30:69-90. 2011
    ....
  2. pmc Dim light at night interacts with intermittent hypoxia to alter cognitive and affective responses
    Taryn G Aubrecht
    Department of Neuroscience and Institute of Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
    Am J Physiol Regul Integr Comp Physiol 305:R78-86. 2013
    ....
  3. pmc Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes
    Imran H Iftikhar
    Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of South Carolina, Columbia, SC, USA
    Ann Am Thorac Soc 10:115-20. 2013
    ..Obstructive sleep apnea (OSA) is an independent risk factor for the development of insulin resistance (IR). Treatment with continuous positive airway pressure (CPAP) for OSA has shown conflicting results on IR...
  4. pmc Agreement in the scoring of respiratory events and sleep among international sleep centers
    Ulysses J Magalang
    Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
    Sleep 36:591-6. 2013
    ..We sought to determine the interrater agreement of PSG scoring among international sleep centers...
  5. pmc Effect of oral appliances on blood pressure in obstructive sleep apnea: a systematic review and meta-analysis
    Imran H Iftikhar
    University of South Carolina, School of Medicine, Columbia, SC, USA
    J Clin Sleep Med 9:165-74. 2013
    ..Oral appliance (OA) therapy is an important alternative therapy to CPAP for patients with mild to moderate OSA...
  6. ncbi Choice of cyclodextrin for cellular cholesterol depletion for vascular endothelial cell lipid raft studies: cell membrane alterations, cytoskeletal reorganization and cytotoxicity
    Adam H Hinzey
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH 43210, USA
    Indian J Biochem Biophys 49:329-41. 2012
    ..Also, the current study offered a safer method of cholesterol removal from membranes and lipid rafts by HPCD, suggesting its use in studies to investigate the role of lipid raft-associated cholesterol in cellular functions...
  7. pmc Selective inhibition of hypoxia-inducible factor 1α ameliorates adipose tissue dysfunction
    Kai Sun
    Touchstone Diabetes Center, Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
    Mol Cell Biol 33:904-17. 2013
    ....
  8. pmc Thiol-redox antioxidants protect against lung vascular endothelial cytoskeletal alterations caused by pulmonary fibrosis inducer, bleomycin: comparison between classical thiol-protectant, N-acetyl-L-cysteine, and novel thiol antioxidant, N,N'-bis-2-mercap
    Rishi B Patel
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA
    Toxicol Mech Methods 22:383-96. 2012
    ..Overall, the results of the current study suggested the central role of thiol-redox in vascular EC dysfunction associated with ILF...
  9. pmc Phytochemical antioxidants modulate mammalian cellular epigenome: implications in health and disease
    Smitha Malireddy
    Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Dorothy M Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA
    Antioxid Redox Signal 17:327-39. 2012
    ..The widely studied epigenetic alterations include DNA methylation, covalent modification of chromatin structure, state of histone acetylation, and involvement of microribonucleic acids...
  10. pmc Curcumin regulates airway epithelial cell cytokine responses to the pollutant cadmium
    Jessica Rennolds
    Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH 43210, United States
    Biochem Biophys Res Commun 417:256-61. 2012
    ..Interestingly, the natural antioxidant curcumin could prevent both cadmium-induced IL-6 and IL-8 secretion by human airway epithelial cells. In conclusion, curcumin could be used to prevent airway inflammation due to cadmium inhalation...
  11. ncbi Eicosanoid signaling and vascular dysfunction: methylmercury-induced phospholipase D activation in vascular endothelial cells
    Shariq I Sherwani
    Lipidomics, Lipid Signaling, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, Dorothy M Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, 473 W 12th Avenue, Columbus, OH, 43210, USA
    Cell Biochem Biophys 67:317-29. 2013
    ..These results offered insights into the mechanism(s) of the MeHg-mediated vascular endothelial cell lipid signaling as an underlying cause of mercury-induced cardiovascular diseases. ..
  12. pmc Novel lipid-soluble thiol-redox antioxidant and heavy metal chelator, N,N'-bis(2-mercaptoethyl)isophthalamide (NBMI) and phospholipase D-specific inhibitor, 5-fluoro-2-indolyl des-chlorohalopemide (FIPI) attenuate mercury-induced lipid signaling leading t
    Jordan D Secor
    Lipid Signaling, Lipidomics, and Vasculotoxicity Laboratory, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Dorothy M Davis Heartand Lung Research Institute and Division of Pharmacology, Colleges of Medicineand Pharmacy, The Ohio State University, Columbus, OH, USA
    Int J Toxicol 30:619-38. 2011
    ..For the first time, this study demonstrated that redox-dependent and PLD-mediated bioactive lipid signaling was involved in mercury-induced vascular EC cytotoxicity which was protected by NBMI and FIPI...
  13. pmc Intermittent hypoxia exacerbates pancreatic β-cell dysfunction in a mouse model of diabetes mellitus
    Shariq I Sherwani
    Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH Dorothy M Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH
    Sleep 36:1849-58. 2013
    ..We hypothesized that IH would exacerbate pancreatic β-cell dysfunction and alter the fatty acids in the male Tallyho/JngJ (TH) mouse, a rodent model of type 2 diabetes...

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. ..