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.
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.
|Collette, Katie M; Zhou, Xu Dong; Amoth, Haley M et al. (2014) Long-term ?1B-adrenergic receptor activation shortens lifespan, while ?1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence. Age (Dordr) 36:9675|
|Papay, Robert S; Shi, Ting; Piascik, Michael T et al. (2013) ??A-adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion. Mol Pharmacol 83:939-48|
|Doze, Van A; Perez, Dianne M (2013) GPCRs in stem cell function. Prog Mol Biol Transl Sci 115:175-216|
|Shi, Ting; Moravec, Christine S; Perez, Dianne M (2013) Novel proteins associated with human dilated cardiomyopathy: selective reduction in ýý(1A)-adrenergic receptors and increased desensitization proteins. J Recept Signal Transduct Res 33:96-106|
|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|
|Doze, Van A; Papay, Robert S; Goldenstein, Brianna L et al. (2011) Long-term *1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Mol Pharmacol 80:747-58|
|Perez, Dianne M; Papay, Robert S; Shi, Ting (2009) alpha1-Adrenergic receptor stimulates interleukin-6 expression and secretion through both mRNA stability and transcriptional regulation: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. Mol Pharmacol 76:144-52|
|Naga Prasad, Sathyamangla V; Duan, Zhong-Hui; Gupta, Manveen K et al. (2009) Unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks. J Biol Chem 284:27487-99|
|Gupta, Manveen K; Papay, Robert S; Jurgens, Chris W D et al. (2009) alpha1-Adrenergic receptors regulate neurogenesis and gliogenesis. Mol Pharmacol 76:314-26|