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

International Journal of Cardiology 167 (2013) 3027–3080

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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d

Letters to the Editor

Upregulation of heme oxygenase-1 expression for protecting against myocardial ischemia and reperfusion injury Xingwei Zhang a, Wenmin Liu a, Ying Jian a, Yu Zhang b, Chang Bian b, Shanxin Liu a,⁎ a b

Department of Cardiology, the Affiliated Hospital of Hangzhou Normal University, #126 Wenzhou Road, Hangzhou, Zhejiang Province 310015, China Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, #88 Jiefang Road, Hangzhou, Zhejiang Province 310009, China

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Article history: Received 1 November 2012 Accepted 11 November 2012 Available online 27 November 2012 Keywords: Heme oxygenase-1 Ischemia and reperfusion injury Signal pathway Traditional Chinese medicinal herbs

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 the molecular mechanism 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, tetramethylpyr-

⁎ Corresponding author. Tel.: + 86 13738158026. E-mail address: [email protected] (S. Liu).

azine, 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 action with 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. References [1] Ryter SW, Otterbein LE, Morse D, Choi AM. Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. Mol Cell Biochem 2002;234–235:249–63. [2] Hu X, Wang J, Jiang H. Heme oxygenase-1: an important therapeutic target for protecting against myocardial ischemia and reperfusion injury. Int J Cardiol 2013;167(2):587–8. [3] Ferrandiz ML, Devesa I. Inducers of heme oxygenase-1. Curr Pharm Des 2008;14:473–86. [4] Liu SX, Zhang Y, Wang YF, et al. Upregulation of heme oxygenase-1 expression by hydroxysafflor yellow A conferring protection from anoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes. Int J Cardiol 2012;160:95–101. [5] Hwa JS, Jin YC, Lee YS, et al. 2-methoxycinnamaldehyde from Cinnamomum cassia reduces rat myocardial ischemia and reperfusion injury in vivo due to HO-1 induction. J Ethnopharmacol 2012;139:605–15.

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Letters to the Editor

[6] Chen SY, Hsiao G, Hwang HR, Cheng PY, Lee YM. Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats. J Biomed Sci 2006;13:731–40. [7] Lee YS, Kang YJ, Kim HJ, et al. Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. Apoptosis 2006;11:1091–100. [8] Wang CY, Chau LY. Heme oxygenase-1 in cardiovascular diseases: molecular mechanisms and clinical perspectives. Chang Gung Med J 2010;33:13–24.

[9] Tron K, Samoylenko A, Musikowski G, et al. Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes. J Hepatol 2006;45:72–80. [10] Wu ML, Ho YC, Yet SF. A central role of heme oxygenase-1 in cardiovascular protection. Antioxid Redox Signal 2011;15:1835–46.

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Circulating microRNAs (miRs) for diagnosing acute myocardial infarction: An exciting challenge Fabiola Olivieri a,b,⁎, Roberto Antonicelli c, Maurizio C. Capogrossi d, Antonio Domenico Procopio a,b a

Dept. of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy Center of Clinical Pathology and Innovative Therapy, Italian National Research Center on Aging INRCA-IRCCS, Ancona, Italy Dept. of Cardiology-CCU, Ospedale “U. Sestilli”, Italian National Research Center on Aging INRCA-IRCCS, Ancona, Italy d Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Roma, Italy b c

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Article history: Received 29 October 2012 Accepted 11 November 2012 Available online 26 November 2012 Keywords: Myocardial infarction MicroRNAs Circulating miRs

The diagnostic relevance of circulating microRNAs (miRs) in acute myocardial infarction (AMI) is a cutting-edge topic both for research and clinical implications. Advances in molecular biology and technology have initiated considerable interest in nucleotide-based biomarkers. The first AMI biomarkers that appeared on the scene were myoglobin, creatine kinase (CK), its isoenzyme MB (CK-MB) and lactate dehydrogenase isoenzyme 1 (LD-1). Even if they are not specific for cardiac muscle damage, they have been used for years to diagnose AMI in patients with chest pain. In the early 90's the situation changed; first creatine kinase MB mass (CK-MB mass) replaced CK-MB activity and subsequently cardiac-specific proteins, cardiac troponins T and I (cTnT and cTnI) displaced LD-1 analysis [1]. Currently, the new generations of high-sensitivity cardiac troponin (hs-cTnT and hs-cTnI) assays detect circulating troponins at concentrations approximately 10-fold lower than older conventional assays, showing excellent diagnostic performances. Thus, hs-cTnT or hs-cTnI evaluations are recommended in AMI diagnosis guidelines [2]. The clinical introduction of hs-cTn assays, however, markedly increased the number of patients presenting with positive hs-cTn values due to pathological conditions other than AMI, such as hypertensive crisis or renal and heart failure. This represents a real problem in differential diagnosis, especially in elderly patients with a modest hs-cTn increase at presentation and with co-morbidities [3]. Another drawback of hs-cTn assays is their inadequate sensitivity during the initial hours after AMI onset, since they achieve their peak 3 to 6 h after the onset of symptoms [4]. Thus, a highly sensitive and specific biomarker is urgently needed to further reduce AMI mortality, especially

⁎ Corresponding author at: Dept. of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Via Tronto 10/A-60020 Ancona, Italy. Tel.: + 39 071 2206242; fax: + 39 071 2206240. E-mail address: [email protected] (F. Olivieri).

among elderly patients with a chest pain of uncertain diagnosis. Recent studies have demonstrated that specific miRs are released from the heart into the coronary circulation following myocardial injury [5]. Since the release of intracellular miRs into the circulation may not be merely a consequence of plasma membrane disruption following cell death, but could be due to an active release in the context of the ischemic-induced response, it can be hypothesized that circulating miRs may be earlier biomarkers of cardiac necrosis [6]. As reported by Lippi et al., different circulating miRs have been described in a variety of studies aimed at quantifying their sensitivity and specificity in AMI diagnosis, e.g. miR499-5p, -133, -208, -1 and -663b [7,8]. However, the magnitude and kinetics of the increase of each of these miRNAs after coronary occlusion differ and there is conflicting evidence on which of these miRNAs is best suited to detect early myocardial injury and has a prognostic value [9]. Thus, the evaluation of the diagnostic performances of pooled miRs is not recommendable. Another limitation of Lippi's study is the heterogeneous diagnosis of the AMI patients (NSTEMI and STEMI) included in the meta-analysis. We previously reported that circulating miR-499-5p exhibited a diagnostic accuracy superior to that of hs-cTnT in the peculiar setting of elderly NSTEMI patients with modest hs-cTnT elevation at presentation [10]. Thus, a meta-analysis with a single miR or with miR signatures obtained in the same setting of AMI patients would have been preferable. Notwithstanding the limitations of the meta-analysis performed by Lippi and co-authors, it confirmed that the diagnostic performance of circulating miRs, when used as a stand-alone test, is globally comparable to that of high-sensitive cTn commercial immunoassays [7]. This result is very encouraging taking into account that circulating miR quantification is currently characterized by some limitations: i) the evaluation of circulating miRs currently requires techniques not completely standardized and automated, ii) there is inconsistency about plasma miR normalization performances and recommendations, and iii) the exact time course of myocardialderived miR release into the bloodstream in AMI patients is still poorly defined. Thus, even if circulating miRs presently offer an interesting and exciting opportunity to improve AMI diagnosis, their use in clinical practice requires a quick, standardized and automated detection system. In conclusion, the results obtained by the pioneering studies on circulating myocardial-derived miRs as biomarkers of AMI, encourage technological advances and larger clinical studies to elucidate their diagnostic ability vs. hs-cTn. At this stage, it is conceivable that a multi-biomarker approach could improve the diagnostic accuracy of AMI, especially in the setting of elderly patients.