Mechanisms of Heme-Oxygenase-1 Cytoprotection for Gene and Cell Based Therapies against Cardiovascular Disease

Abstract

Establishing the cellular and molecular basis for cardiovascular disease and the application of tools to manipulate the cardiovascular system genetically provide potential for new forms of treatment against cardiovascular disease, including: atherosclerosis, myocardial ischemia, cardiac hypertrophy and heart failure. Heme oxygenase-1 (HO-1) is an enzyme that has potential for the treatment of cardiovascular diseases (CVD). Atherosclerotic plaques express high levels of HO-1. Advanced plaques are stabilized in part through the separation of plaque constituents from the blood by the fibrous cap made up of smooth muscle cells. Protection of smooth muscle cells from apoptosis in the fibrous cap may be a means of promoting plaque stability in patients. Here we show that expression of HO-1 in human vascular smooth muscle cells renders them resistant to apoptosis mediated by oxidative stress. The cytoprotective mechanism mediated by HO-1 is mediated in part through protein kinase B (Akt). Plaque rupture may lead to myocardial infarction. Tissue recovery after mycocardial infarction requires neovascularization for improved tissue perfusion. A novel cell type recently discovered in the circulation has been characterized as an endothelial progenitor cell (EPC) and appears capable of promoting neovascularization of post-infarct tissue, thereby enhancing tissue recovery and perfusion. Most EPCs transplanted into the infarct environment do not survive or are not retained to function in neovascularization. Here we show that expression of HO-1 and its cytoprotective partner Akt protect EPCs in an infarct environment and promote EPC function in an infarct environment. Oxidative stress can result in maladaptive cardiomyocyte hypertrophy. In a model of oxidative stress-induced myocyte hyperterophy we demonstrate the expression of HO-1 prevents cellular hypertrophy through antioxidant mechanisms and regulation of the transcription nuclear factor kappa B (NF-κB). Atherosclerotic plaque vulnerability is determined by the composition of the lesion. We demonstrate that HO-1 deficient mice have more calcified and fibrotic lesions. This may have implications in the management of late stage atherosclerosis. Collectively, this work demonstrates new insights into the molecular mechanisms of cardiovascular cells under stress that may have implications for strategies aimed at treating CVD using HO-1.