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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL031113-23A1
Application #
8439504
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
1983-07-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
23
Fiscal Year
2013
Total Cost
$380,000
Indirect Cost
$130,000
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
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