Intracoronary Cytoprotective Gene Therapy

Abstract

BACKGROUND Vascular endothelial growth factor-B (VEGF-B) activates cytoprotective/antiapoptotic and minimally angiogenic mechanisms via VEGF receptors. Therefore, VEGF-B might prove an ideal candidate for the treatment of dilated cardiomyopathy, which displays modest microvascular rarefaction and increased rate of apoptosis. OBJECTIVES We evaluated VEGF-B gene therapy in a canine model of tachypacing-induced dilated cardiomyopathy. METHODS Chronically instrumented dogs underwent cardiac tachypacing for 28 days. Adeno-associated-9 viral vectors carrying VEGF-B167 genes were infused intracoronarily at the beginning of the pacing protocol or during compensated heart failure (HF). Moreover, we tested a novel VEGF-B167 transgene controlled by the atrial natriuretic factor (ANF) promoter. RESULTS Compared to controls, VEGF-B167 markedly preserved diastolic and contractile function and attenuated ventricular chamber remodeling, halting the progression from compensated to decompensated HF. ANF-VEGF-B167 expression was low in normo-functioning hearts and stimulated by cardiac pacing; thus, it functioned as an ideal therapeutic transgene, active only under pathological conditions. CONCLUSIONS Our results, obtained with a standard technique of interventional cardiology in a clinically relevant animal model, support VEGF-B167 gene transfer as an affordable and highly effective new therapy for nonischemic HF.

VEGF-B promotes recovery of corneal innervations and trophic functions in diabetic mice

“…In line with our results, previous studies provided evidence for VEGF-B conferring neuroprotection via free radical scavenging28. Moreover, in vitro study also showed that VEGF-B treatment could ameliorated ROS generation in cardiomyocytes in response to both angiotensin II and norepinephrine40.…”

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

“…Importantly, this large-animal model allows chronic delivery of 3OHB via an indwelling catheter in the right ventricle together with in vivo measurements of hemodynamics and myocardial substrate metabolism. The graded tachypacing protocol results in severe and predictable cardiac decompensation over a period of approximately 4 weeks (30). Starting on day 13 of pacing, when cardiac function was still in the compensated stage, 3OHB was infused continuously into the right ventricle until the end of the protocol (day 29 of pacing), resulting in a steady-state arterial plasma concentration of approximately 2.5-fold higher than that measured in an untreated historical control HF group used for comparison in this study (Supplemental Figure 5A).…”

“…Surgical instrumentation. Thirteen male mongrel dogs (aged 9-12 months; 21-27 kg) were chronically instrumented with a solid state pressure gauge inserted in the left ventricle, 3 fluid-filled catheters (1 inserted in the descending thoracic aorta, 1 in the right ventricle, and 1 in the left atrium), a Doppler flow probe placed around the left circumflex coronary artery, and 2 pacing leads attached to the LV epicardial surface, as previously described (22,30). The dogs wore cotton/nylon jackets to protect the exteriorized wires and catheters.…”

MicroRNA‐30c suppresses the pro‐fibrogenic effects of cardiac fibroblasts induced by TGF‐β1 and prevents atrial fibrosis by targeting TGFβRII

“…Notably, miR‐30c up‐regulation was inversely correlated with the decreased expression levels of Col I and Col3α1 in cells treated with TGF‑β1. ECM metabolic imbalance is involved in various cardiovascular diseases such as myocardial infarction, heart failure and AF 68, 69, 70. Moreover, miR‐30c overexpression decreased the ECM‐regulated gene expression levels of Col I and Col3α1 in CFs, whereas MiR‐30c inhibition promoted these processes.…”