Heme Oxygenase-1 Upregulation: A Novel Approach in the Treatment of Cardiovascular Disease

Abstract

Significance: Heme oxygenase (HO) plays a pivotal role in both vascular and metabolic functions and is involved in many physiological and pathophysiological processes in vascular endothelial cells (ECs) and adipocytes. Recent Advances: From the regulation of adipogenesis in adipose tissue to the adaptive response of vascular tissue in the ECs, HO plays a critical role in the capability of the vascular system to respond and adjust to insults in homeostasis. Recent studies show that HO-1 through regulation of adipocyte and adipose tissue functions ultimately aid not only in local but also in systemic maintenance of homeostasis. Critical Issues: Recent advances have revealed the existence of a cross talk between vascular ECs and adipocytes in adipose tissue. In the pathological state of obesity, this cross talk contributes to the condition's adverse chronic effects, and we propose that specific targeting of the HO-1 gene can restore signaling pathways and improve both vascular and adipose functions. Future Directions: A complete understanding of the role of HO-1 in regulation of cardiovascular homeostasis is important to comprehend the homeostatic regulation as well as in cardiovascular disease. Efforts are required to highlight the effects and the ability to target the HO-1 gene in models of obesity with an emphasis on the role of pericardial fat on cardiovascular health. Antioxid. Redox Signal. 32, 1045-1060.

OX-HDL: A Starring Role in Cardiorenal Syndrome and the Effects of Heme Oxygenase-1 Intervention

“…In animal models of myocardial ischemia (MI), both overexpression and pharmacological induction of HO-1 reduce infarct size and ventricular remodeling after ischemia-reperfusion damage by improving cardiac metabolism [ 143 ]. Increased HO-1 expression has a protective effect against ischemia-reperfusion injury in the kidney [ 144 ] and can correct blood pressure elevation following ang-II exposure [ 145 ].…”

Targeting Heme Oxygenase-1 in the Arterial Response to Injury and Disease

“…Furthermore, SMCs isolated from HO-1-deficient mice exhibit greater rates of cell growth relative to cells derived from wild-type animals. Moreover, induction of HO-1 by many endogenous factors and pharmaceutical compounds blocks the proliferation of vascular SMCs [10][11][12][13][14][15][16][17][18]. The inhibition of SMC growth by HO-1 is associated with an increase in p21 expression and the arrest of SMCs in the G 0 /G 1 phase of the cell cycle, whereas inhibition of HO-1 activity promotes cell cycle progression [34,35].…”

“…As previously reviewed [10][11][12][13][14][15][16][17][18]149], many vanguard drugs used to treat cardiovascular disease stimulate the expression of HO-1, including statins, aspirin, nitrates, sildenafil, rapamycin, and paclitaxel. Furthermore, the induction of HO-1 by these drugs is speculated to contribute to their clinical efficacy.…”

“…Given the important contribution of vascular SMCs to arterial remodeling, the targeting of these cells offers a possible strategy for therapeutic intervention. Accumulating evidence over the past three decades has identified the enzyme heme oxygenase-1 (HO-1) as a critical regulator of cardiovascular health and disease [10][11][12][13][14][15][16][17][18]. Diverse mechanisms appear to mediate the protective actions of HO-1 in the circulation, including anti-inflammatory and antioxidant effects; anti-thrombotic actions; inhibition of vasomotor tone; and its ability to modulate the growth, function, and survival of vascular cells.…”

Induction of Heme Oxygenase-1 Modifies the Systemic Immunity and Reduces Atherosclerotic Lesion Development in ApoE Deficient Mice

“…A higher level of HO-1 in monocyte-derived macrophages was related to the unstable phenotype of atherosclerotic plaques featured with higher content of macrophage, thin fibrous caps, and thrombosis ( Fiorelli et al, 2019 ). HO-1’s anti-atherogenic properties may also be mediated through free radicals scavenging, fatty acid oxidation inhibition, lipid composition modification, or influence on the nitric oxide pathway ( Durante, 2011 ; Bellner et al, 2020 ). In addition to its antioxidant effects, HO-1 has been widely reported to have anti-inflammatory effects in atherosclerosis.…”