Inhibition of cardiac fibrosis in myocardial infarction

Abstract

The described invention provides a method for treating myocardial infarction (MI) in a subject comprising administering to the subject a therapeutic amount of a pharmaceutical composition comprising a polypeptide of amino sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof made from a fusion between a first polypeptide that is a cell permeable protein (CPP) selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 2), WLRRIKAWLRRIKA (SEQ ID NO: 21), WLRRIKA (SEQ ID NO: 22), YGRKKRRQRRR (SEQ ID NO: 23), FAKLAARLYR (SEQ ID NO: 25), and KAFAKLAARLYR (SEQ ID NO: 26), and a second polypeptide that is a therapeutic domain (TD), and a pharmaceutically acceptable carrier. The described invention also provides a kit comprising a composition comprising at least one MK2 inhibitor peptide; a means for administering the composition; and a packaging material.

1 .- 24 . (canceled) 
     
     
         25 . A method for treating myocardial infarction (MI) in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutic amount of a pharmaceutical composition comprising a polypeptide of amino sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof made from a fusion between a first polypeptide that is a cell permeable protein (CPP) selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 2), WERRIKAWERRIKA (SEQ ID NO: 21), WERRIKA (SEQ ID NO: 22), YGRKKRRQRRR (SEQ ID NO: 23), FAKLAARLYR (SEQ ID NO: 25), and KAFAKLAARLYR (SEQ ID NO: 26), and a second polypeptide that is a therapeutic domain (TD), and a pharmaceutically acceptable carrier, wherein the therapeutic amount is effective to reduce regions of fibrosis at a site of ischemic insult, to reduce non-ischemic site of fibrosis, or a combination thereof compared to an untreated control subject suffering from MI. 
     
     
         26 . The method of  claim 25 , wherein the MI is acute myocardial infarction (AMI). 
     
     
         27 . The method of  claim 25 , wherein the therapeutic amount is effective to inhibit MK2. 
     
     
         28 . The method of  claim 25 , wherein the therapeutic amount is effective to increase ejection fraction. 
     
     
         29 . The method of  claim 25 , wherein the therapeutic amount is effective to increase fractional shortening. 
     
     
         30 . The method of  claim 25 , wherein the therapeutic amount is effective to decrease left ventricular dilation. 
     
     
         31 . The method of  claim 25 , wherein the therapeutic amount is effective to inhibit apoptotic cell death of cardiomyocytes, enhance cell death of cardiac fibroblasts, or a combination thereof. 
     
     
         32 . The method of  claim 25 , wherein the cardiac fibrosis is reduced by 50% compared to the untreated control subject. 
     
     
         33 . A method for treating ischemia in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutic amount of a pharmaceutical composition comprising a polypeptide of amino sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof made from a fusion between a first polypeptide that is a cell permeable protein (CPP) selected from the group consisting of a polypeptide of amino acid sequence YARAAARQARA (SEQ ID NO: 2), WERRIKAWERRIKA (SEQ ID NO: 21), WERRIKA (SEQ ID NO: 22), YGRKKRRQRRR (SEQ ID NO: 23), FAKLAARLYR (SEQ ID NO: 25), and KAFAKLAARLYR (SEQ ID NO: 26), and a second polypeptide that is a therapeutic domain (TD), and a pharmaceutically acceptable carrier, wherein the therapeutic amount is effective to inhibit caspase activity, enhance lactate dehydrogenase (LDH) release, inhibit heterogeneous nuclear ribonucleoprotein AO (HNRNPA0) expression or any combination thereof in cardiomyocytes. 
     
     
         34 . The method according to  claim 33 , wherein the caspase activity is caspase 3/7 activity. 
     
     
         35 . The method according to  claim 33 , wherein the therapeutic amount is effective to enhance caspase activity, inhibit lactate dehydrogenase (LDH) release, inhibit heterogeneous nuclear ribonucleoprotein AO (HNRNPA0) expression or any combination thereof in primary cardiac fibroblasts.