Compositions and methods for the treatment of myocardial ischemia/reperfusion injury with Annexin A1 short peptide

#The present invention relates to compositions and methods for the treatment of myocardial ischemia/reperfusion injury using Annexin AI (ANXA1)-related peptides.

#Perioperative myocardial injury (PMI) secondary to ischemia/reperfusion (I/R) remains a major cause of cardiovascular morbidity and mortality following cardiac surgery and transplantation, and is further exacerbated by acute hyperglycemia. Hyperglycemic exacerbation of PMI significantly blocks the cardioprotective effect afforded by glucose-insulin-potassium (GIK). To date, there is not an effective treatment or prevention of perioperative myocardial injury due to ischemia/reperfusion.

#Annexin A1 (ANXA1), a 37 kDa protein, is a member of the annexin superfamily, which consists of 13 calcium and phospholipid binding proteins with a significant degree of biological and structural homology (40-60%). ANXA1, originally identified as a mediator of the anti-inflammatory effects of glucocorticoids, has diverse biological functions including the regulation of inflammatory pathways, cell proliferation machinery, cell death signaling, and the process of carcinogenesis. Altering the expression or the localization of this protein can contribute to the pathogenesis of human diseases including inflammatory diseases, cardiovascular diseases and cancer. It has been demonstrated that ANXA1 reduces the leukocyte-dependent myocardial damage associated with myocardial I/R injury (La et al. (2001) FASEB J. 15(12):2247-2256). The functional link between migrated leukocytes and the myocardial damage was confirmed, and significantly lower numbers of extravasated leukocytes were counted in the group of rats treated with ANXA1 (La, M. et al. supra).

#The foregoing objects, features and advantages of the present invention will become more apparent from a reading of the following description in connection with the accompanying drawings in which:

#FIG. 1 is a graph showing the effect of ANXA1 N-terminus short peptides Ac-QAW, Ac-KQAW (SEQ ID NO:3), Ac-AMVSEFLKQAWFIENEEQEYVQYVK (SEQ ID NO:10), Ac-FLK, Ac-EFLKQAW (SEQ ID NO:6) and Ac-VSEFLKQAW (SEQ ID NO:9) on NF-kB activation in human pancreatic cancer cell lines. Values presented are means±SD; n=5; *P<0.05 and #P<0.001 vs. control (0). Ac=acetylation.

#FIGS. 2A-C show results demonstrating that ANXA1sp attenuates LPS-induced NIH 3T3 cell death by inhibiting nuclear factor kappa B NF-κB proinflammatory pathways. FIG. 2A is a graph showing the effect of ANXA1sp on NF-κB activity over time on NIH 3T3 cells activated with LPS alone and LPS+peptide. FIG. 2B is a graph showing the effect of ANXA1sp on interleukin-6 (IL-6) production over time by NIH 3T3 cells activated with LPS alone and LPS+peptide. FIG. 2C shows images of NIH 3T3 cells over time activated with LPS or LPS+peptide.

#The present invention is based on the surprising and unexpected discovery that ANXA1sp peptide is effective in treating and/or preventing myocardial ischemia/reperfusion injury and in treating and/or preventing perioperative myocardial injury secondary to ischemia reperfusion injury. Thus, in one embodiment, the present invention provides a method of treating myocardial ischemia/reperfusion injury in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of an ANXA1sp peptide.

#Also provided herein is a method of ameliorating myocardial ischemia/reperfusion injury in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of an ANXA1sp peptide.

#Further provided herein is a method of preventing myocardial ischemia/reperfusion injury in a subject (e.g., a subject in need thereof), comprising administering to the subject an effective amount of an ANXA1sp peptide.