VEGF165 Gene Therapy Improves Left Ventricular Function and Exercise Capacity in Diabetic Rats after Myocardial Infarction: Impact on Mortality Rate

Abstract

Despite the increased amount of evidence about the benefits of human vascular endothelial growth factors by plasmid (pHuVEGF 165 ) based gene transfer after an ischemic event, the effects of pHuVEGF 165 therapy in diabetic hearts after myocardial infarction (MI) remains poorly investigated. We evaluated the effects of intramyocardial pHuVEGF 165 injection on left ventricular (LV) morphometry, function and blood flow, maximal oxygen consumption (VO 2 max), and the total mortality rate of diabetic rats after MI. Male Wistar rats were divided into control (C), myocardial infarction+saline injection (I+SAL), myocardial infarction+pHuVEGF 165 injection (I+VEGF), diabetes+myocardial infarction+saline injection (DI+SAL), and diabetes+myocardial infarction+pHuVEGF 165 injection (DI+VEGF). MI was induced after 15 days of streptozotocin diabetes induction. One day after MI, the animals received pHuVEGF 165 or saline intramyocardial injection. LV function and maximal oxygen consumption (VO 2 max) were evaluated at the initial injection and 30 days after injections. MI area evaluation showed an additional reduction in DI+VEGF (8±1%) in comparison with group I+VEGF (31±3%). Improvement in systolic function, evaluated invasively and noninvasively, lung wet/dry weight ratio, and VO 2 max were observed in both pHuVEGF 165 injected groups. Consequently, mortality rate was reduced in I+VEGF (19%) and DI+VEGF (12.5%) when compared with I+SAL (48%) and DI+SAL (37.5%) groups. In conclusion, pHuVEGF 165 therapy resulted in reduced MI area, stabilization and maintenance of left ventricular function, increased VO 2 max, and reduced mortality in MI animals, diabetic or not. These results highlight the importance of continuing experimental studies and controlled clinical trials of gene therapy for ischemic cardiomiopathy associated with the pathological conditions of diabetes.

Role of Exercise Training on Autonomic Changes and Inflammatory Profile Induced by Myocardial Infarction

“…In recent years, our laboratory has investigated the changes induced by MI alone [ 25 , 27 ] or associated with different risk factors, such as hypertension [ 69 , 70 ], ovarian hormone deprivation [ 23 ], sinoaortic denervation [ 24 ], and diabetes [ 26 – 28 , 71 – 73 ]. These studies have also tested different therapeutic approaches in the management of MI-induced changes.…”

“…These studies have also tested different therapeutic approaches in the management of MI-induced changes. Among these therapeutic approaches, some deserve greater emphasis: therapy involving stem cells and mesenchymal bone marrow both in situ [ 70 ] and intravenously [ 69 ], gene therapy with vascular endothelium-derived growth factor (VEGF) [ 73 ], and ET [ 22 , 23 , 25 , 27 ].…”