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.

Keywords: adipocytes; cardiovascular disease; heme oxygenase; obesity; oxidative stress.

FIG. 1.

Induction of HO-1 improves vascular reactivity. Schematic depicting improved vascular reactivity in HFD-fed mice in which the HO-1 system has been induced (5, 25). Images of mice modified from the study of Li et al. (77), in which HO activity was induced by administration of CoPP. CoPP, cobalt protoporphyrin IX; HFD, high-fat diet; HO-1, heme oxygenase-1. Color images are available online.

FIG. 2.

Scheme illustrating some of the effects observed in cardiac function after manipulation of HO-1 levels. (A) Reversal of post-ischemic influx of inflammatory cells (53), (B) increased incidence of ischemia–reperfusion-induced ventricular fibrillation (17), (C) increased cardiac allograft survival (39), and (D) increased long-term survival and reduced myocardial fibrosis and scarring after acute myocardial infarction (80). AAV, adenoassociated virus; rAAV, recombinant adenoassociated virus; ZnPPIX, zinc protoporphyrin IX. Color images are available online.

FIG. 3.

Pharmacological or genetic induction of HO-1-EET-PGC-1α axis. Schematic depicting pharmacological or genetic induction of HO-1-EET-HO-1α axis (121, 133), as well as a decrease in HO-1 transcriptional suppressor, BACH-1 (24, 121, 123, 129). HO-1-PGC-1α-1EET feedback loop and some of the important effects observed systemically (reduced oxidative stress and inflammation), and in the vasculature (dilation) and adipose tissues (prevention or reversal of differentiation, and reduced inflammation). Also included are some of the effects observed on a subcellular level, that is, increased mitochondrial thermogenesis and biogenesis. Based on the HO-1-PGC-1α-EET axis action on adipocytes, the impaired exosomal secretion is likely increased with reversal of adipocyte dysfunction. BACH-1, BTB domain and CNC homolog 1; EET, epoxyeicosatrienoic acid; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Color images are available online.

FIG. 4.

Cross talk between adipocytes and vascular endothelial cells. Scheme illustrating the cross talk between vascular endothelial cells and adipocytes in both healthy and pathological states. Gene therapy targets that have been studied are indicated. Color images are available online.

FIG. 5.

Effect of HO-1 and PGC-1α expression on left ventricular fractional shortening. Gene expression profiling revealing similar expression levels of (A) PGC-1α and (B) HO-1 in epicardial and visceral fat depots of obese humans and mice. (C) Normalized left ventricular fractional shortening in obese+HO-1-induced mice. *Different from the corresponding control. Color images are available online.

FIG. 6.

Schematic depiction of how obesity and increased ROS levels give rise to inflamed dysfunctional visceral (including pericardial) adipose tissue, which altogether drives inflammation of the intraorgan (including epicardial) adipose tissues. There is a significant reduction in HO-1, PGC-1α, and adiponectin, in visceral and pericardial fat of obese mice, and obese humans with coronary disease when compared with same fat depots of lean mice and age- and gender-matched human controls, respectively. This imbalance causes a shift in the signaling molecule-content of adipocyte-secreted exosomes from supporting homeostasis to disruption thereof. This is accompanied by a reciprocal increase in levels of inflammatory cytokines in intraorgan fat depots, including epicardial fat, that causes organ dysfunction and disruption of homeostasis. ROS, reactive oxygen species. Color images are available online.