Methods and compositions for regulating srca2a expression levels in myocardial infarction

Abstract

The disclosure provides methods and compositions for increasing SERCA2a expression levels in a mammalian subject in need thereof. The methods comprise administering to the subject a therapeutic amount of an aromatic-cationic peptide to subjects in need thereof. In some embodiments, the aromatic-cationic peptide is D-Arg-2′6′-Dmt-Lys-Phe-NH2, or a pharmaceutically acceptable salt thereof such as acetate or trifluoroacetate salt. In some embodiments, the subject has suffered a myocardial infarction.

What is claimed is: 
     
         1 . A method for increasing SERCA2a expression in a mammalian subject in need thereof, comprising administering to the mammalian subject a therapeutically effective amount an aromatic-cationic peptide, wherein the aromatic-cationic peptide comprises D-Arg-2′6′-Dmt-Lys-Phe-NH 2 , or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the subject has suffered a myocardial infarction. 
     
     
         3 . The method of  claim 2 , wherein the myocardial infarction results from hypertension; ischemic heart disease; exposure to a cardiotoxic compound; myocarditis; thyroid disease; viral infection; gingivitis; drug abuse; alcohol abuse; pericarditis; atherosclerosis; vascular disease; hypertrophic cardiomyopathy; acute myocardial infarction; left ventricular systolic dysfunction; coronary bypass surgery; starvation; an eating disorder; or a genetic defect. 
     
     
         4 . The method of  claim 1 , wherein the aromatic-cationic peptide is administered about 0.5 hours to 4 hours after myocardial infarction. 
     
     
         5 . The method of  claim 1 , wherein the increase of SERCA2a expression prevents, ameliorates, or treats LV remodeling. 
     
     
         6 . The method of  claim 1 , wherein the increase of SERCA2a expression increases LV function compared to a control subject not administered the aromatic-cationic peptide. 
     
     
         7 . The method of  claim 6 , wherein increased LV function is determined by one or more physiological measures factors from the group consisting of reduced LV stroke volume, improved LV ejection fraction, improved fractional shortening, reduced infarct expansion, improved hemodynamics, and reduced lung volumes. 
     
     
         8 . The method of  claim 1 , wherein the subject is a human. 
     
     
         9 . The method of  claim 1 , wherein the peptide is administered orally, topically, systemically, intravenously, subcutaneously, intraperitoneally, or intramuscularly. 
     
     
         10 . The method of  claim 1 , further comprising separately, sequentially or simultaneously administering a cardiovascular agent to the subject. 
     
     
         11 . The method of  claim 10 , wherein the cardiovascular agent is selected from the group consisting of: an anti-arrhthymia agent, a vasodilator, an anti-anginal agent, a corticosteroid, a cardioglycoside, a diuretic, a sedative, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II antagonist, a thrombolytic agent, a calcium channel blocker, a thromboxane receptor antagonist, a radical scavenger, an anti-platelet drug, a β-adrenaline receptor blocking drug, α-receptor blocking drug, a sympathetic nerve inhibitor, a digitalis formulation, an inotrope, captopril, and an antihyperlipidemic drug.