Upregulation of heme oxygenase-1 expression for protecting against myocardial ischemia and reperfusion injury

Abstract

Myocardial ischemia and reperfusion (I/R) injury is frequently encountered in clinical practice because of the wide utilization of percutaneous coronary intervention in acute myocardial infarction caused by coronary thrombosis. Heme oxygenase-1 (HO-1) or heat shock protein 32, the rate-limiting enzyme responsible for the breakdown of heme into free ferrous iron, carbon monoxide, and bilirubin, confers protection against cellular stress [1]. Several studies indicated that the upregulation of HO-1 expression could provide a protective effect on myocardial I/R injury. Thus, HO-1 is regarded as an important therapeutic target for protecting against myocardial I/R injury [2]. Searching and exploiting the inducers of HO-1, understanding the signal pathways that induce HO-1, and determining themolecularmechanism behind the beneficial effects of HO-1 may facilitate the development of novel drugs and methods for protecting against myocardial I/R injury. Numerous clinical and experimental pharmacologic compounds, such as heme, anoxia, hyperxia, heavy metals, inflammatory factors, statins, proton pump inhibitors, and sevoflurane, reportedly induce HO1 expression [3]. Several active ingredients of traditional Chinese medicinal herbs are utilized to reduce myocardial I/R injury in clinical practice, some of their effects exert probably through inducing HO-1 expression. Understanding the mechanism behind their protective effects is essential to promote their clinical application.We reported that hydroxysafflor yellow A, a chemical compound isolated from Carthamus tinctorius L, could upregulate the expression of HO-1 and confer protection against anoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes [4]. The active ingredients of traditional Chinese medicinal herbs such as 2-methoxycinnamaldehyde, tetramethylpyrazine, and higenamine were also proved that could induce HO-1 expression and attenuate myocardial I/R injury in rats [5–7]. The mitogen-activated protein kinase-activated signal pathway and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB, Akt) signal pathway, and signaling molecules such as protein kinase C and tyrosine kinase are involved in HO-1 regulation [8]. The janus protein tyrosine kinase/signal transducer and activator of transcription signal pathway certified the pathway via which regulation of HO-1 expression by interleukin-6 in rat hepatocytes [9]. Our recent study has shown that hydroxysafflor yellow A could upregulate the expression and activity of HO-1 through the PI3K/Akt/nuclear factor erythroid-2-related factor 2 pathway in H9c2 cardiomyocytes [4]. The mechanism by which several active ingredients of traditional Chinese medicinal herbs such as 2-methoxycinnamaldehyde, tetramethylpyrazine, and higenamine induce HO-1 expression to attenuate myocardial I/R injury through the signal transduction pathway should be further studied. The protective function of HO-1 against myocardial I/R injury was demonstrated by the utilization of pharmacological methods and genetic approaches in experiment research and clinical practice [10]. Searching and exploiting new inducers of HO-1, activating the signal pathways that induce HO-1, and using gene therapy are the strategies that we can utilize to protect against myocardial I/R injury through this important therapeutic target. Monomers of traditional Chinese medicinal herbs have multiple effects and multiple mechanism of actionwith few side effects. Exploiting the inducers of HO-1 from traditional Chinese medicinal herbs and studying its mechanism of action will provide more options for protecting against myocardial I/R injury. The authors of this manuscript have also certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.