ИСТИНА

Funding Acknowledgements: Russian science foundation #16-15-00181 Chronic heart failure (HF) continues the most important problem of modern medicine. Despite many advances in the management of HF, treatment options for many patients remain limited and new treatment strategies are clearly needed. Gene therapy and therapeutic vascular growth may provide a new treatment option for these patients. The aim of the present study is to analyse the potential of combined HGF and VEGF gene therapy for stimulation of endogenous mechanisms of cardiac repair after myocardial infarction. As a proof-of concept we have tried to evaluate VEGF, HGF and HGF+VEGF plasmid based gene delivery to rat ischemic myocardium. We have found that within 14 days post injection combination of VEGF+HGF plasmids was superior to single VEGF or HGF in terms of vascular density increase (both capillary and arteriole), but was unable to significantly reduce post-infarction fibrosis, yet certain trend was observed. HGF and HGF+VEGF injections significantly stimulate accumulation of c-kit+ resident cardiac stem cells in border zone andWT1+epicardial cell activation in compare to VEGF plasmid injections. We have also found the reduction of inflammatory cellular infiltration of border zone in VEGF+HGF group compared to VEGF group, which might indicate decrement of inflammatory response in myocardium. In further in vitro studies using HUVEC and TIME endothelial cells we found that production of pro-inflammatory chemokines MCP-1 and IL-6 is increased by recombinant VEGF and reduced after addition of HGF. Combination of both factors resulted in medium levels of MCP-1 and IL-6 production, thus HGF seems to counteract the pro-inflammatory action of VEGF. As for pro-angiogenic IL-8, both factors had stimulating effect on its production and their combination yielded maximum amount of IL-8 expression and secretion by endothelial cell cultures, which suggests an alternative way for IL-8 regulation involved. As a result of the study we can conclude that combination of VEGF and HGF has good translational promise for myocardial repair and regeneration. Deeper in-sights into their mechanism of action might show non-canonical properties and modes of action of that combination that may drive its way into practice.