The overall goal of this project is to validate a novel molecular target for treatment of heart failure (HF) and its underlying cause, cardiomyopathy (CM). HF is an extremely common and serious medical problem in the United States, but so far no new drugs have resulted from 30 years of basic research. This project will test the hypothesis that a drug activating the alpha-1A-adrenergic receptor (AR), at a very low dose, can prevent or improve CM and HF, by increasing contractility, protecting from cardiac muscle cell death and fibrosis, and stimulating adaptive growth and gene expression. The catecholamines norepinephrine (NE) and epinephrine (EPI) activate two types of ARs on cardiac muscle cells, the dominant beta-ARs, which increase heart contraction, and alpha-1-ARs, which are few in number and have been mostly overlooked. In HF, when NE and EPI are high, beta-AR stimulation can be damaging, so beta-AR-blockers are standard therapy. Alpha-1-ARs are relatively unoccupied in HF. However, a body of old and new information, from studies in animals and in man, now supports the novel idea that the alpha-1A subtype comprises an endogenous adaptive and protective mechanism in myocytes. New, preliminary data show that a drug with very high affinity for the alpha-1A can prevent or improve CM in several mouse models. The new data also show that alpha-1A-ARs are present on a specialized sub-population of myocytes, and that the """"""""fetal gene program"""""""" in CM and HF might be adaptive, rather than maladaptive as thought now. Two main aims are planned, one translational, and one mechanistic, to confirm and expand these new ideas.
Aim I will test very low doses of highly selective and potent alpha-1A agonists in mouse models of CM, including toxic CM (the cancer drug doxorubicin), ischemic CM (post-myocardial infarction), and pressure overload CM (transverse aortic constriction). Physiological and molecular studies will assess efficacy, safety, and specificity, the last using alpha-1-AR knockout mice. Consensus requirements for successful translation will be followed, including study of females, older mice, and mice with co-morbid conditions (diabetes and obesity).
Aim II will test the cellular and contractile mechanisms of alpha-1A activation in the CM models. Physiological studies will define the underlying mechanisms of increased systolic contraction, and test if diastolic function is impaired. Cell and molecular studies, including flow cytometry, will focus on the sub- populations of myocytes that have fetal genes and alpha-1A-ARs, and will test whether they stimulate down- stream growth factors to cause adaptive growth of myocytes and myocardium. Successful completion of these Aims will provide essential pre-clinical validation of a potential new therapy in CM and HF, and will define a novel endogenous alpha-1A protective and adaptive mechanism in cardiac myocytes.
Heart failure, which leads to trouble breathing and fatigue, is one of the most common, serious medical problems in the United States. It has caused about 1 million hospital admissions each year since 1997, and is fatal in 20% of patients within 1 year of diagnosis. A 40-year old man or woman has a 20% chance of developing heart failure. Despite these serious statistics, no new drugs for heart failure have been proved for many years. The goal of this project is to validate a potential new way to treat heart failure. Successful completin of the project will be the initial step to develop a new drug.
|Beak, JuYoun; Huang, Wei; Parker, Joel S et al. (2017) An Oral Selective Alpha-1A Adrenergic Receptor Agonist Prevents Doxorubicin Cardiotoxicity. JACC Basic Transl Sci 2:39-53|
|Myagmar, Bat-Erdene; Flynn, James M; Cowley, Patrick M et al. (2017) Adrenergic Receptors in Individual Ventricular Myocytes: The Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent. Circ Res 120:1103-1115|
|López, Javier E; Sharma, Janhavi; Avila, Jorge et al. (2017) Novel large-particle FACS purification of adult ventricular myocytes reveals accumulation of myosin and actin disproportionate to cell size and proteome in normal post-weaning development. J Mol Cell Cardiol 111:114-122|
|López, Javier E; Jaradeh, Katrin; Silva, Emmanuel et al. (2017) A method to increase reproducibility in adult ventricular myocyte sizing and flow cytometry: Avoiding cell size bias in single cell preparations. PLoS One 12:e0186792|
|Simpson, Paul C; Myagmar, Bat-Erdene; Swigart, Philip M et al. (2017) Response by Simpson et al to Letter Regarding Article, ""Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent"". Circ Res 120:e56-e57|
|Thomas, R Croft; Singh, Abhishek; Cowley, Patrick et al. (2016) A Myocardial Slice Culture Model Reveals Alpha-1A-Adrenergic Receptor Signaling in the Human Heart. JACC Basic Transl Sci 1:155-167|
|Cowley, Patrick M; Wang, Guanying; Chang, Audrey N et al. (2015) The ?1A-adrenergic receptor subtype mediates increased contraction of failing right ventricular myocardium. Am J Physiol Heart Circ Physiol 309:H888-96|
|Simpson, Paul C (2015) A New Pathway for Sympathetic Cardioprotection in Heart Failure. Circ Res 117:592-5|
|Shimkunas, Rafael; Makwana, Om; Spaulding, Kimberly et al. (2014) Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone. Am J Physiol Heart Circ Physiol 307:H1150-8|
|O'Connell, Timothy D; Jensen, Brian C; Baker, Anthony J et al. (2014) Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66:308-33|
Showing the most recent 10 out of 59 publications