SRF Phosphorylation and the Progression to Heart Failure

Smoking is toxic to the heart and blood vessels due to the numerous injurious chemicals that are inhaled, including nicotine and carbon monoxide. Tobacco use thereby increases the risk that smokers and others exposed secondhand to tobacco smoke will have atherosclerosis and heart disease, including heart attacks and sudden death. Those who survive a heart attack or have other cardiovascular diseases like high blood pressure are likely to develop heart failure. Heart failure is characterized by shortness of breath, decreased exercise tolerance and fatigue, and fluid retention, such as swelling of the ankles or “wet lungs” (pulmonary edema). Heart failure is currently associated with a 50% chance of death within 5 years of the onset of symptoms despite improvements in the care of heart failure patients and the use of such drugs as ACE inhibitors and beta-blockers. We have been studying how the heart muscle reacts to stress in disease in an attempt to identify new cellular proteins that may be targeted by new heart failure drugs. We have identified a novel property of a protein called SRF that regulates how genes are expressed in the cardiac myocyte, the cell type responsible for heart pumping action. We have found that SRF is altered in models of heart disease in a way such that this modification may contribution to the enlargement of the heart in heart failure. In this grant, we will be studying how SRF is regulated in heart failure, and we will test new approaches to restore normal SRF function and prevent heart failure. In particular, we will testing two new biologic drugs that may be useful in preventing heart failure. We will test these biologic drugs in small rodent models of heart attacks (myocardial infarction) and high blood pressure. In combination with basic molecular and cellular biology research that will reveal how SRF function is altered in the stressed heart, we expect to define SRF as a novel drug target for heart failure therapies.