Original articleβ-Blocker carvedilol protects cardiomyocytes against oxidative stress-induced apoptosis by up-regulating miR-133 expression
Introduction
Cardiovascular disease is the main cause of death and birth defects all over the world [1]. Oxidative stress is one of the common responses to cardiac injuries in a variety of cardiovascular diseases [2]. Over-production of oxidative stress causes damage to a variety of cellular macromolecules, including lipids, DNA and proteins [3]. Increased ROS level contributes critically to the advance of atherosclerosis, hypertension, heart failure and acute myocardial infarction (MI) [4]. Oxidative stress is a major inducer of cardiomyocyte apoptosis [5]. However, the mechanisms underlying oxidative stress-induced apoptosis in cardiomyocytes are poorly understood.
It has been well recognized that microRNAs (miRNAs, miRs) play a central role in regulating some key protein-coding genes related to cardiovascular disease [6], [7], [8], [9], [10]. Among the known miRNAs, miR-133 is found to be specifically expressed in adult cardiac and skeletal muscles [11], [12]. Recent functional studies indicate that miR-133 produces an anti-apoptotic effect, protecting cardiomyocytes against apoptotic cell death under stress [13].
β-Adrenergic blockers have been widely used for the treatment of cardiovascular diseases, such as hypertension, hyperlipidemia, and coronary heart disease, especially for preventing sudden cardiac death in patients suffering acute or chronic MI [14], [15], [16]. Carvedilol, a nonselective β-adrenoceptor antagonist, is a multiple-action drug that has potent antioxidant properties [17]. Several experimental models of ischemia–reperfusion (IR) have already underlined the cardioprotective effects of carvedilol [18]. Although studies have shown that carvedilol also inhibits cardiomyocyte apoptosis [19], the exact mechanism is still unknown. In this study, we investigated whether carvedilol protects cardiomyocyte from apoptosis by influencing miRNA under pathological conditions relevant to human cardiac disease.
Section snippets
Ethics statement
This study was approved by the Ethic Committees of the Harbin Medical University. Experimental procedures were approved by the Animal Care and Use Committee of Harbin Medical University, and conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Rat model of myocardial infarction (MI) and drug administration
Healthy male Wistar rats (200–250 g) were used and kept under standard animal room conditions at room temperature (23 ± 1 °C), with constant humidity of 55
Carvedilol ameliorates impaired cardiac function of infarct rats
To explore the potential role of carvedilol in MI, we evaluated cardiac function by echocardiography as shown in Fig. 1A. The ejection fraction (EF%) and fractional shortening (FS%) were significantly declined to 38.4 ± 5.3% and 19.4 ± 3.0%, respectively, in the MI group, while they were increased to 60.7 ± 3.7% and 33.8 ± 2.8%, respectively, in the MI + Car group (Figs. 1B and C). The results strongly indicated that carvedilol plays a protective role in MI rats.
MiR-24, -133, -145, -210, -494, and -499
Discussion
In this study, we made an effort to understand whether miRNA is involved in the long recognized cytoprotective effects of carvedilol, a β-blocker. The main findings of this study include: (1) carvedilol ameliorated the impaired cardiac function of infarct rats and up-regulated miR-133 expression in vivo; (2) carvedilol markedly up-regulated miR-133 expression in the presence of oxidative stress and reduced oxidative stress-induced cardiomyocyte apoptosis; and (3) knockdown of miR-133 by its
Conclusions
As a whole, our study revealed that carvedilol produced cardioprotective effects by preventing oxidative stress-induced apoptosis of cardiomyocytes. The beneficial effects were at least partially mediated by up-regulating miR-133, resulting in caspase-9/caspase-3 downregulation.
Disclosures
All authors declare that they have no competing interests for this study.
Acknowledgments
We thank Prof Baofeng Yang for his constructive suggestions to improve the quality of the paper. This work was supported in part by the Funds for Creative Research Groups [81121003] and the Major Program [81230081] of National Natural Science Foundation of China, the National Nature Science Foundation of China [grant numbers 81001434, 81270042, 30901208], and the Funds for Harbin Science and Technology Foundation [2009RFQXS006].
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Contributed equally to this work.