Our objective is to understand differential signal transduction paradigms by which a1 -adrenergic receptor (AR) subtypes mediate protection versus damage in the heart. a1-AR subtypes (a1A, a1B and a1D) are G protein-coupled receptors that mediate the sympathetic nervous system by binding catecholamines. However, little is known about specific subtype functions. Our research has suggested that a1-AR signaling pathways may contribute to either cardioprotection or damage. a1-AR antagonists were initially thought to be useful in treating heart failure due to sympathetic overload. However, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, the use of a non-selective a1-AR antagonist worsened heart failure and increased mortality. In contrast, carvedilol, an antagonist of a1- and ?-ARs but with higher affinity for the a1B-AR subtype, provides an effective treatment for chronic heart failure, suggesting that subtype-specific signaling may contribute to these differential effects of a1-AR blockade. Because of the use of a1-AR antagonists in prostatic disease, its increasing potential for treating drug abuse and neurodegeneration, determining the role of a1-AR subtypes in the heart has very important clinical implications. Our laboratory had made unique transgenic mice of the a1-AR subtypes and demonstrated differential regulation of cardiovascular function. We have published that the a1A-AR but not the a1B-AR protected the heart from ischemic injury. Chronic a1B-AR stimulation resulted in heart dysfunction, and inflammation. We have determined unique pathways that are differentially regulated by the a1-AR subtypes, such as apoptosis, STAT3 activation, and cytokine secretion, which may explain how the a1-AR subtypes differentially control cardiac adaptation. Our research may lead to the development of new therapeutic strategies to treat heart failure and ischemia. This proposal focuses on a1-AR subtypes in the heart and differential RGS/GRK scaffolds coupling to different PKC/MAPK isoforms, explaining why a1A-AR stimulation is protective while chronic stimulation of the a1B-AR promotes cardiac damage.

Public Health Relevance

This proposal will demonstrate and determine the mechanism by which the a1A- adrenergic receptor can protect the heart against ischemia and induce an adaptive hypertrophy that protects against apoptosis. In light of clinical trials which indicate that blockage of a1-ARs is deleterious for heart failure, but are commonly used to treat prostatic hyperplasia, we need to determine the exact roles of the a1-AR subtypes in cardiac regulation using animal models that will give definitive answers.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098279-03
Application #
8257899
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Adhikari, Bishow B
Project Start
2010-07-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Shi, Ting; Papay, Robert S; Perez, Dianne M (2016) α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake. J Recept Signal Transduct Res 36:261-70
Collette, Katie M; Zhou, Xu Dong; Amoth, Haley M et al. (2014) Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence. Age (Dordr) 36:9675
Shi, Ting; Moravec, Christine S; Perez, Dianne M (2013) Novel proteins associated with human dilated cardiomyopathy: selective reduction in α(1A)-adrenergic receptors and increased desensitization proteins. J Recept Signal Transduct Res 33:96-106
Doze, Van A; Perez, Dianne M (2013) GPCRs in stem cell function. Prog Mol Biol Transl Sci 115:175-216
Papay, Robert S; Shi, Ting; Piascik, Michael T et al. (2013) α₁A-adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion. Mol Pharmacol 83:939-48
Doze, Van A; Perez, Dianne M (2012) G-protein-coupled receptors in adult neurogenesis. Pharmacol Rev 64:645-75
Shi, Ting; Papay, Robert S; Perez, Dianne M (2012) ýý(1A)-adrenergic receptor differentially regulates STAT3 phosphorylation through PKCýý and PKCýý in myocytes. J Recept Signal Transduct Res 32:76-86
Grisanti, Laurel A; Perez, Dianne M; Porter, James E (2011) Modulation of immune cell function by ýý(1)-adrenergic receptor activation. Curr Top Membr 67:113-38
Perez, Dianne M; Doze, Van A (2011) Cardiac and neuroprotection regulated by ýý(1)-adrenergic receptor subtypes. J Recept Signal Transduct Res 31:98-110
Doze, Van A; Papay, Robert S; Goldenstein, Brianna L et al. (2011) Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Mol Pharmacol 80:747-58

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