PKC Signaling in cAMP-Induced Pulmonary Vasodilation

Summary

Principal Investigator: SCOTT BARMAN
Abstract: Idiopathic Pulmonary Arterial Hypertension (IPAH) is a disease of unknown origin that results in narrowing of the pulmonary arteries causing high pulmonary blood pressure often leading to heart failure. Currently, there is little knowledge on the cellular and molecular foundation of IPAH. Normally, signaling mechanisms which elevate cAMP and cGMP in the pulmonary vasculature maintain a low pressure, high perfusion environment. Activation of large-conductance, calcium- and voltage-activated potassium (BKCa) channels is important in the regulation of pulmonary arterial pressure and inhibition of BKCa channels has been implicated in pulmonary hypertension. Published studies from our laboratory in pulmonary arterial smooth muscle cells (PASMC) of the Fawn-Hooded rat (FHR), an animal model of pulmonary hypertension, show that cAMP, an activator of cAMP-dependent protein kinase (PKA), opens BKCa channels through "cross-activation" of cGMP-dependent protein kinase (PKG), which is inhibited by protein kinase C (PKC) activators. In contrast, PKC activation opens BKCa channels in (normotensive control) PASMC of Sprague-Dawley rats (SDR). New preliminary data indicate that specific PKC isozymes are differentially expressed in normotensive and hypertensive PASMC, and that PKC and PKG regulation of BKCa channel activity requires the expression and phosphorylation of specific sites on BKCa channel subunits. Therefore, the hypothesis of the proposed studies is that specific PKC isozymes differentially regulate BKCa channel activity in normotensive and hypertensive pulmonary arterial smooth muscle via targeted PKC and PKG phosphorylation sites on BKCa channel subunits. This hypothesis will be tested using current techniques of electrophysiology, vascular contraction, and biochemistry/molecular biology to determine in normotensive and hypertensive PASMC: 1) mechanisms of PKC regulation of BKCa channels, 2) the relationship of BKCa channel subunit expression to protein kinase (PKA, PKC, PKG)-mediated function, and 3) mechanisms of phosphorylating specific subunit sites that elicit regulatory effects of PKA, PKC and PKG on BKCa channel activity. The long-term goal is to determine how PKC regulates the effect of cAMP-elevating agents in pulmonary arterial smooth muscle. Progress of these studies will provide important knowledge towards the development of novel therapeutic agents that will help reduce the morbidity and mortality associated with pulmonary hypertension.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Effect of PKC isozyme inhibition on forskolin-induced activation of BKCa channels in rat pulmonary arterial smooth muscle
    Shu Zhu
    Department of Pharmacology and Toxicology, Medical College of Georgia, 1170 15th street, Augusta, Georgia 30912, USA
    Lung 184:89-97. 2006
  2. ncbi Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling
    Guichun Han
    Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912 2300, USA
    Am J Physiol Heart Circ Physiol 293:H314-21. 2007
  3. ncbi Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C
    Scott A Barman
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA
    Am J Physiol Lung Cell Mol Physiol 293:L472-9. 2007
  4. pmc Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle
    Shu Zhu
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Ther Adv Respir Dis 2:119-27. 2008
  5. pmc Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle
    Guichun Han
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USA
    J Pharmacol Exp Ther 329:850-5. 2009
  6. pmc Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells
    Shu Zhu
    Dept of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA
    Am J Physiol Lung Cell Mol Physiol 297:L758-66. 2009
  7. pmc RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension
    Scott A Barman
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Vasc Health Risk Manag 5:663-71. 2009
  8. pmc Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women
    Richard E White
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, United States
    Steroids 75:788-93. 2010
  9. pmc Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle
    Xuan Yu
    Michael E DeBakey Institute Division of Women s Health, Texas A and M University, College Station, Texas, 77843, USA
    Am J Physiol Endocrinol Metab 301:E882-8. 2011

Scientific Experts

Detail Information

Publications9

  1. ncbi Effect of PKC isozyme inhibition on forskolin-induced activation of BKCa channels in rat pulmonary arterial smooth muscle
    Shu Zhu
    Department of Pharmacology and Toxicology, Medical College of Georgia, 1170 15th street, Augusta, Georgia 30912, USA
    Lung 184:89-97. 2006
    ....
  2. ncbi Nongenomic, endothelium-independent effects of estrogen on human coronary smooth muscle are mediated by type I (neuronal) NOS and PI3-kinase-Akt signaling
    Guichun Han
    Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912 2300, USA
    Am J Physiol Heart Circ Physiol 293:H314-21. 2007
    ..These findings now provide a molecular mechanism that can explain the clinical observation that estrogen enhances coronary blood flow in patients with diseased or damaged coronary arteries...
  3. ncbi Vasoconstrictor effect of endothelin-1 on hypertensive pulmonary arterial smooth muscle involves Rho-kinase and protein kinase C
    Scott A Barman
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA
    Am J Physiol Lung Cell Mol Physiol 293:L472-9. 2007
    ..These results suggest that both PKC and Rho/Rho-kinase mediate the heightened pulmonary vascular response to ET-1 in hypertensive pulmonary arterial smooth muscle...
  4. pmc Role of phosphodiesterases in modulation of BKCa channels in hypertensive pulmonary arterial smooth muscle
    Shu Zhu
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Ther Adv Respir Dis 2:119-27. 2008
    ....
  5. pmc Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle
    Guichun Han
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, USA
    J Pharmacol Exp Ther 329:850-5. 2009
    ..These findings indicate an essential role for Hsp90 in nongenomic estrogen signaling in CASM and further suggest that Hsp90 might represent a prospective therapeutic target to enhance estrogen-stimulated cardiovascular protection...
  6. pmc Mutation of protein kinase C phosphorylation site S1076 on alpha-subunits affects BK(Ca) channel activity in HEK-293 cells
    Shu Zhu
    Dept of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA
    Am J Physiol Lung Cell Mol Physiol 297:L758-66. 2009
    ....
  7. pmc RhoA/Rho-kinase signaling: a therapeutic target in pulmonary hypertension
    Scott A Barman
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA
    Vasc Health Risk Manag 5:663-71. 2009
    ....
  8. pmc Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women
    Richard E White
    Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, United States
    Steroids 75:788-93. 2010
    ..Further, this molecular mechanism is consistent with recent analyses revealing that HRT produces salutary effects in younger women, but mainly increases the risk of cardiovascular dysfunction in older postmenopausal women...
  9. pmc Activation of G protein-coupled estrogen receptor induces endothelium-independent relaxation of coronary artery smooth muscle
    Xuan Yu
    Michael E DeBakey Institute Division of Women s Health, Texas A and M University, College Station, Texas, 77843, USA
    Am J Physiol Endocrinol Metab 301:E882-8. 2011
    ..This novel action of estrogen-like compounds may help clarify some of the controversy surrounding the vascular effects of estrogens...