Cardiac hypertrophy is a critical determinant of cardiac remodeling and the progression of heart failure. Heart failure remains a major public health problem and effective therapies are limited. Molecular signaling involved in cardiac hypertrophy is complex and involves a number of cell surface receptors, signal transduction pathways and nuclear factors. An emerging theme in signal transduction is the concept of microdomains that contain cell surface receptors and intracellular signaling molecules and provide order to signaling pathways. Caveolae are specialized microdomains containing the structural proteins, caveolins that bind, organize and regulate receptors and signaling molecules involved in numerous cell functions including cell growth and hypertrophy. Knocking out the gene for the muscle specific isoform of caveolin (Caveolin-3, Cav-3) results in cardiac hypertrophy and cardiomyopathy. Conversely, overexpression of Cav-3 in cardiac myocytes blocks adrenergic agonist and endothelin-1 induced myocyte hypertrophy. Thus, loss of Cav-3 is sufficient to induce a molecular program resulting in cardiac hypertrophy and cardiomyopathy and overexpression of Cav-3 may be a means to negatively regulate cardiac hypertrophy. Atrial natriuretic peptide (ANP) has diuretic, natriuretic, and vasodilatory properties that inhibit cardiac hypertrophy. A relationship between ANP, caveolae and caveolins was proposed nearly two decades ago. ANP is present within caveolae, closely associated with Cav-3 and may be secreted via caveolae from cardiac myocytes. The preliminary data show that cardiac myocyte-specific overexpression of Cav-3 produces a cardiac phenotype with dramatically increased expression of ANP in the left ventricle at baseline and a reduction in cardiac hypertrophy, increased survival and preserved cardiac function in the face of left ventricular pressure overload. The proposal is designed to address the hypothesis that Cav-3 modulates ANP expression to reduce cardiac hypertrophy and heart failure and to evaluate overexpression of Cav-3 as a unique and beneficial means to modulate ANP expression and treat heart failure patients. The following aims will be pursued:
Aim 1 : Will determine mechanisms for Cav-3 modulation of ANP and ANP coupled signaling in cardiac hypertrophy and heart failure.
Aim 2 : Will determine if conditional cardiac myocyte-specific overexpression of Cav-3 modulates ANP and ameliorates heart failure induced by pressure overload.
Aim 3 : Will determine if gene transfer of Cav-3 modulates ANP and shows efficacy in a preclinical model of heart failure in swine. State of the art molecular and physiological techniques will be used in the studies in clinically relevant models of hypertrophy and heart failure in large and small animal models to focus on mechanism and produce important preclinical data to support potential clinical trials on caveolins as novel therapeutics for heart failure patients.

Public Health Relevance

Project Narrative Prevalent cardiovascular diseases such as chronic hypertension and ischemic heart disease result in cardiac hypertrophy and the development of congestive heart failure. Heart failure is associated with high mortality and morbidity and poor quality of life. Heart failure affects nearly 5 million Americans and is listed on 1 out of every 8 death-certificates in the United States. Heart failure is a primary focus of the VA quality enhancement research initiative (QUERI) and remains the number one discharge diagnosis in the VA healthcare system. The work described in this proposal focuses on elucidating mechanisms to support the use of caveolin proteins as novel therapeutic targets for heart failure patients and is of relevance to the VA patient care mission.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Cardiovascular Studies A (CARA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
VA San Diego Healthcare System
San Diego
United States
Zip Code
Patel, Hemal H; Roth, David M (2018) No pain, no gain: balancing central versus peripheral benefits of analgesics in the age of the opioid crisis. Br J Pharmacol 175:855-856
Ichikawa, Yasuhiro; Zemljic-Harpf, Alice E; Zhang, Zheng et al. (2017) Modulation of caveolins, integrins and plasma membrane repair proteins in anthracycline-induced heart failure in rabbits. PLoS One 12:e0177660
Egawa, Junji; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma. FASEB J 31:3403-3411
Kassan, Adam; Egawa, Junji; Zhang, Zheng et al. (2017) Caveolin-1 regulation of disrupted-in-schizophrenia-1 as a potential therapeutic target for schizophrenia. J Neurophysiol 117:436-444
Mandyam, Chitra D; Schilling, Jan M; Cui, Weihua et al. (2017) Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice. Biol Psychiatry 81:101-110
Kassan, Adam; Pham, Uyen; Nguyen, Quynhmy et al. (2016) Caveolin-3 plays a critical role in autophagy after ischemia-reperfusion. Am J Physiol Cell Physiol 311:C854-C865
Schilling, Jan M; Horikawa, Yousuke T; Zemljic-Harpf, Alice E et al. (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28
See Hoe, Louise E; Schilling, Jan M; Busija, Anna R et al. (2016) Chronic ?1-adrenoceptor blockade impairs ischaemic tolerance and preconditioning in murine myocardium. Eur J Pharmacol 789:1-7
Schilling, Jan M; Roth, David M; Patel, Hemal H (2015) Caveolins in cardioprotection - translatability and mechanisms. Br J Pharmacol 172:2114-25
Sun, Junhui; Nguyen, Tiffany; Aponte, Angel M et al. (2015) Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc Res 106:227-36

Showing the most recent 10 out of 24 publications