Abstract 18778: Myocardial Gene Therapy by Adeno-HSPA12B Administration Induces Angiogenesis and Prevents Ventricular Dysfunction Following Acute Myocardial Infarction in Type I Diabetic Rats
Introduction: Molecular chaperones/heat shock proteins (HSPs) are important regulators of angiogenesis. HSPA12B, a member of HSP70 sub-family 12 predominantly expressed in endothelial cells is required for angiogenesis. In the present study we examined the effects of overexpressing HSPA12B on angiogenesis and myocardial function by intramyocardial administration of adenovirus encoding HSPA12B (Ad. HSPA12B) in a myocardial infarction (MI) model in streptozotocin induced Type I diabetic rats.
Methods: The rats were divided into 6 groups. 1) Control Sham (CS), 2) CMI+Ad.LacZ (CLZMI), 3) CMI+Ad.HSPA12B (CMI-HSPA12B), 4) Diabetic Sham (DS), 5) DMI+Ad.LacZ (DLZMI), 6) DMI+Ad.HSPA12B (DMI-HSPA12B). Following left anterior descending coronary artery ligation Ad.LacZ or Ad.HSPA12B was injected at 4 border zone sites to either CLZMI/DLZMI or CMI-HSPA12B /DMI-HSPA12B group.
Results: We observed increases in capillary (2245±37.2 (n=4) vs 1732±102.5 (n=3); p<0.05) & arteriolar (19±0.5 (n=3) vs 14±0.5 (n=6); p<0.05) density (counts/mm2) in the DMI-HSPA12B compared to the DLZMI group. Formalin-fixed mid-ventricular tissue sections stained with Picrosirius red, exhibited a 44% decrease in collagen deposition in DMI-HSPA12B compared to DLZMI hearts. Echocardiography at 30 days revealed decreased left ventricular inner diameter (systole) (6.3±0.3 vs. 8.5±0.3 (n=6); p<0.05) & increased ejection fraction (51±0.6 vs. 32±0.9 (n=6); p<0.05) & fractional shortening (27±0.4 6 vs. 16±0.5 6 (n=6); p<0.05) in the DMI-HSPA12B compared to DLMI group. Western blot analysis showed increased expression of HSPA12B (1.4 fold) and VEGF (1.4 fold) 4 days after HSPA12B gene delivery in the DMI-HSPA12B group compared to the DLZMI group.
Conclusion: Targeted delivery of HSPA12B induced angiogenesis and improved hemodynamic function in a rat model. Our novel approach may be a viable therapeutic modality in the treatment of diabetes related cardiac failure by stabilizing the myocardium, promoting neovascularization & augmenting protective as well as regenerative responses in ischemic rat myocardium.
- © 2012 by American Heart Association, Inc.