Increased cardiac Ang II activity from intracellular or interstitial formation (autocrine/paracrine mechanisms) is a cause of cardiac hypertrophic remodeling, arrhythmias, and fibrosis. RAS inhibitors are less effective in blocking Ang II-mediated adverse cardiac remodeling because its production within cardiac myocytes follows non-canonical pathways and the plasma membrane imposes a significant barrier to the external environment. The overarching hypothesis of this Program Project Grant is that the non-canonical pathway for intracellular cardiac Ang II production is mediated by a non-renin/ACE pathway. Cardiac chymase, incorporated into these cells from activated mast cells, acts on an endogenously shorter form of angiotensinogen (Aogen) -angiotensin-(1-12) [Ang-(1-12)] - to generate Ang II. The Project leaders' complementary clinical and basic science expertise in this renewal application will address this concept by examining the intracellular pathways and mechanisms accounting for the chymase-mediated Ang II formation and matrix metalloproteinase activation, the potential role of kallikrein as the Ang-(1-12) generating enzyme from Aogen, and the provocative new finding that estrogen deficiency, by modulating the cardiac intracellular chymase/Ang-(1-12) axis, contributes to the adverse cardiac remodeling and left ventricular diastolic dysfunction in postmenopausal women. The integrated research plan employs genetic models of well characterized altered cardiac function and structure (SHR and congenic mRen2.Lewis hypertensive rats; Projects 1 and 3), a cardiac myocyte cell line (HL-1) that maintains cardiac-specific phenotypes, and human left atrial tissue and cardiac pericardial fluid from subjects undergoing cardiac surgery for the correction of mitral regurgitation (Project 2). The additional novel inclusion of studies in rats expressing the human genes for Aogen, chymase, or both will eventually provide a translational laboratory paradigm for unraveling the cellular and biochemical mechanisms of the distinct biotransformation processes by which the human heart regulates production of Ang II in health and disease. Overall, the combined tightly focused efforts of Drs. Ferrario (Project 1), Dell'Italia (Project 2) and Groban (Project 3) will shed new light on the molecular mechanisms of cardiac Ang II contribution to adverse remodeling and progression to heart failure, the distinct ways by which human and rodent cardiac myocytes differ in terms of the cellular pathways for Ang II production, and how chymase and Ang-(1-12) are regulated by estrogen. These discoveries will identify new therapeutic approaches of higher efficacy when compared to angiotensin converting enzyme inhibitors and Ang II receptor blockers.

Public Health Relevance

/RELEVANCE Because clinical evidence does not support meaningful differences in the reduction of cardiovascular risks and events between renin angiotensin system (RAS) inhibitors and other antihypertensive agents, there is consensus that blood pressure control is the main factor counteracting the risk of cardiovascular mortality. This Program Project Grant seeks to show that the relative failure of RAS blockade to achieve greater success is due to the fact that cardiac Ang II synthesis occurs through mechanisms that are independent of renin and angiotensin converting enzyme and rely upon the intracellular and interstitial activity of heart chymase acting on a newly discovered shorter form of the angiotensinogen substrate.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL051952-21A1
Application #
8793998
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Maric-Bilkan, Christine
Project Start
1997-04-01
Project End
2020-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
21
Fiscal Year
2015
Total Cost
$1,744,692
Indirect Cost
$596,993
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Dell'Italia, Louis J; Collawn, James F; Ferrario, Carlos M (2018) Multifunctional Role of Chymase in Acute and Chronic Tissue Injury and Remodeling. Circ Res 122:319-336
Ahmad, Sarfaraz; Ferrario, Carlos M (2018) Chymase inhibitors for the treatment of cardiac diseases: a patent review (2010-2018). Expert Opin Ther Pat 28:755-764
Wang, Hao; Sun, Xuming; Lin, Marina S et al. (2018) G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress. Transl Res 199:39-51
Ahmad, Sarfaraz; Sun, Xuming; Lin, Marina et al. (2018) Blunting of estrogen modulation of cardiac cellular chymase/RAS activity and function in SHR. J Cell Physiol 233:3330-3342
Li, Tiankai; Zhang, Xiaowei; Cheng, Heng-Jie et al. (2018) Critical role of the chymase/angiotensin-(1-12) axis in modulating cardiomyocyte contractility. Int J Cardiol 264:137-144
Guichard, Jason L; Rogowski, Michael; Agnetti, Giulio et al. (2017) Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure. Am J Physiol Heart Circ Physiol 313:H32-H45
Brosnihan, K Bridget; Chappell, Mark C (2017) Measurement of Angiotensin Peptides: HPLC-RIA. Methods Mol Biol 1527:81-99
Butts, Brittany; Goeddel, Lee A; George, David J et al. (2017) Increased Inflammation in Pericardial Fluid Persists 48 Hours After Cardiac Surgery. Circulation 136:2284-2286
Wang, Hao; Sun, Xuming; Chou, Jeff et al. (2017) Cardiomyocyte-specific deletion of the G protein-coupled estrogen receptor (GPER) leads to left ventricular dysfunction and adverse remodeling: A sex-specific gene profiling analysis. Biochim Biophys Acta Mol Basis Dis 1863:1870-1882
da Silva, Jacqueline S; Gabriel-Costa, Daniele; Wang, Hao et al. (2017) Blunting of cardioprotective actions of estrogen in female rodent heart linked to altered expression of cardiac tissue chymase and ACE2. J Renin Angiotensin Aldosterone Syst 18:1470320317722270

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