Angiogenetic Potential of Ad2/Hif-1α/Vp16 after Regional Application in a Preclinical Pig Model of Chronic Ischemia

Abstract

Retroinfusion of Ad2/Hif-1α/VP16, combining a master pro-angiogenic protein with regional myocardial application, may offer an efficient approach to cardiac gene therapy of chronic ischemic cardiomyopathy.

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

“…Blood flow measurements were performed at rest and under increased heart rate (130 bpm). Fluorescence content was analysed via Tecan Saphire 2 micro plate reader and calculation of the regional myocardial blood flow was performed, either as ml g À 1 tissue absolute or as the ratio to the nonischaemic region at rest (blood flow % non-ischaemic) 1,50 .…”

Hypoxia-Inducible Factor 1 and Cardiovascular Disease

“…In a porcine model of coronary artery stenosis, pressure-regulated retroinfusion of the great cardiac vein with an adenovirus that encoded a fusion protein consisting of the amino-terminal half of HIF-1α (which contains the dimerization and DNA-binding domains) fused to VP16 (a herpesvirus transactivator) was associated with an increased number of angiographically detectable collateral vessels and with increased myocardial function (30). However, a clinical trial failed to demonstrate increased myocardial perfusion in patients who were undergoing coronary artery bypass graft surgery and who received this gene therapy (31).…”

“…However, a clinical trial failed to demonstrate increased myocardial perfusion in patients who were undergoing coronary artery bypass graft surgery and who received this gene therapy (31). Although the age of the pigs used in the animal study was not stated (30), it is likely that the researchers used young animals that did not appropriately model the age of the clinical population. Studies of combined AdCA5 and BMDAC therapy in aged animal models of myocardial ischemia are needed to inform the design of future clinical trials.…”

Cardiocytoprotection Perspectives With Ischemic Preconditioning: Hypoxia-Induced Factor 1 — Possible Molecular Mechanism and Target for Pharmacotherapy

“…В экспериментальной модели коронарного стеноза удалось достичь увеличения числа коллатеральных сосудов, определяемых по результатам ангиографии, и повышения функций миокарда с помощью инфузии раствора, содержащего аденовирус, кодирующий сложный белок, состоящий из аминотерминальной половины HIF-1α (содержащей димеризационные и дезоксирибонуклеиновая кислота (ДНК)-связывающие домены) и трансактиватора герпесвируса (VP16) по большой кардиальной вене [30]. Тем не менее, сопоставимое клиническое исследование не продемонстрировало увеличение перфузии миокарда у пациентов, которым выполнено аортокоронарное шунтирование, в сравнении с соответствующей генной терапией [31].…”