Heme Oxygenase-1 and the Vascular Bed: From Molecular Mechanisms to Therapeutic Opportunities

Abstract

Heme oxygenase-1, an enzyme degrading heme to carbon monoxide, iron, and biliverdin, has been recognized as playing a crucial role in cellular defense against stressful conditions, not only related to heme release. HO-1 protects endothelial cells from apoptosis, is involved in blood-vessel relaxation regulating vascular tone, attenuates inflammatory response in the vessel wall, and participates in blood-vessel formation by means of angiogenesis and vasculogenesis. The latter functions link HO-1 not only to cardiovascular ischemia but also to many other conditions that, like development, wound healing, or cancer, are dependent on neovascularization. The aim of this comprehensive review is to address the mechanisms of HO-1 regulation and function in cardiovascular physiology and pathology and to demonstrate some possible applications of the vast knowledge generated so far. Recent data provide powerful evidence for the involvement of HO-1 in the therapeutic effect of drugs used in cardiovascular diseases. Novel studies open the possibilities of application of HO-1 for gene and cell therapy. Therefore, research in forthcoming years should help to elucidate both the real role of HO-1 in the effect of drugs and the clinical feasibility of HO-1-based cell and gene therapy, creating the effective therapeutic avenues for this refined antioxidant system.

The Flavanol (−)-Epicatechin Prevents Stroke Damage through the Nrf2/HO1 Pathway

“…A number of cerebral ischemia studies indicate that neuroprotective agents exert an effect through the Nrf2 detoxifying pathway (Satoh et al, 2006;Shih et al, 2005;Zhao et al, 2006). This pathway has also been suggested to be at least partially mediated through HO1 induction by electrophiles (Gong et al, 2002;Itoh et al, 2004;Loboda et al, 2008). Our finding that Nrf2 À/À mice were not protected against ischemic damage provides additional evidence that the protective effect of EC is mediated by activating the Nrf2/HO1 pathway.…”

HO-1 Induced by Cilostazol Protects Against TNF-α-associated Cytotoxicity via a PPAR-γ-dependent Pathway in Human Endothelial Cells

“…HO-1 is the inducible form of HO that catalyzes the rate-limiting step of the conversion of heme into biliverdin, CO, and free iron. HO-1 and its products exert anti-apoptotic, anti-inflammatory, anti-oxidant, and pro-angiogenic effects in the vasculature [3,25]. HO-1 is up-regulated in endothelial cells and vascular smooth muscle cell (VSMC) by PPAR-α and PPAR-γ agonists in vitro [23].…”

Post-conditioning with sevoflurane induces heme oxygenase-1 expression via the PI3K/Akt pathway in lipopolysaccharide-induced acute lung injury

“…The human HO-1 gene is localized on chromosome 22q12 and consists of five exons and four introns, spanning 14-kb (21,22). A promoter sequence is located ~28 base pairs upstream from the starting site of transcription, which contains a number of enhancer and transcriptional regulatory elements, including the antioxidant response element (ARE), heat shock element and hypoxic response element.…”