Minocycline improves cardiac function after myocardial infarction in rats by inhibiting activation of PARP-1

Abstract

To investigate whether Minocycline can protect myocardial cells after myocardial infarction and improve myocardial remodeling through inhibiting PARP-1 activity, thus improving cardiac function. 50 male Wistar rats aged 4 months were used to establish the myocardial infarction model. The experimental rats underwent the echocardiography at 3 d, 14 d and 28 d after operation. After 28 days, the rats were executed and the myocardial tissues in the infarct-related zone were treated with immumohistochemical staining and molecular biology detection. Our study found Minocycline could improve the cardiac function of rats after myocardial infarction. TUNEL results showed that Minocycline could reduce the apoptosis of myocardial cells after myocardial infarction. Western blotting results showed that Minocycline reduced the expressions of apoptotic proteins. Immunohistochemistry and Western blotting showed that Minocycline reduced the expressions of inflammatory factors, NF-κB and IL-1β, etc., in myocardial cells after myocardial infarction. Besides, it was found in further study that Minocycline could inhibit the PARP-1 activity after myocardial ischemic necrosis. In conclusion, Myocardial remodeling occurs after myocardial infarction, affecting the cardiac function. Minocycline can inhibit the activity of apoptosis and inflammatory factors, reduce the apoptosis, alleviate the inflammation and improve the ventricular remodeling through inhibiting PARP-1, thus protecting the cardiac function.

Introduction

With the wide application of emergency thrombolysis, emergency percutaneous transluminal coronary angioplasty (PTCA) and emergency coronary artery bypass surgery, the mortality rate of acute myocardial infarction has been greatly reduced, but the incidence rate of heart failure after myocardial infarction has been increasingly higher. Changes in hemodynamics, neuroendocrine activation, inflammatory response and apoptosis after myocardial ischemic and anoxic necrosis will contribute to the ventricular remodeling and lead to abnormalities in the cardiac structure and function. Myocardial remodeling after myocardial infarction is the main pathogenic factor of heart failure [1], [2], seriously affecting the life quality and survival rate of patients. Apoptosis [3], [4] and inflammatory response [5], [6] play important roles in the occurrence and development of ventricular remodeling.

Poly-(ADP-ribose) polymerase-1 (PARP-1) is involved in the physiological and pathological processes of damage repair of a variety of cells [7], [8]. It is closely related to the occurrence and development of many cardiovascular diseases [9], [10]. PARP-1 is a kind of DNA repair enzyme existing in most eucaryons, which regulate the cell survival and apoptosis. It can identify the damaged DNA and bind to it, and then participate in the DNA damage repair. PARP-1 lose the enzyme activity after cleaved by Caspase, which is the core member of apoptosis, and thus affecting the stability of cells and promoting the occurrence of apoptosis. The excessive activation of PARP-1 will lead to the rapid consumption of intracellular NAD+ and ATP, eventually causing dysfunction and necrosis of cells due to energy depletion. In addition, PARP-l can also regulate the expressions of a variety of inflammatory factors, among which nuclear factor-κB (NF-κB) is involved mostly in these processes. The activation of PARP-1 is associated with the pathological process of various cardiovascular and cerebrovascular diseases, including congestive heart failure, hypertensive stroke, diabetes mellitus, cerebral ischemia, atherosclerotic endothelial dysfunction, heart failure after myocardial infarction and cancer, etc. But the inhibition of PARP-1 expression can protect the vascular endothelial functions in hypertension, atherosclerosis and stroke, etc., and improve the cardiac function, which is also helpful for the treatment of diabetes mellitus and cancer [11], [12].

Minocycline is a kind of tetracycline derivative, clinically used primarily for the treatment of acne and other skin infections. In addition to the antibacterial capability, it has been shown in recent years that Minocycline has the anti-inflammatory and cytoprotective effects [13], [14]. As a kind of neuroprotective agent, Minocycline has a protective effect in various experimental models of neurological diseases [15], [16]. In these studies, Minocycline was thought to have a direct effect of reducing inflammation and apoptosis. Recently, it has been reported that Minocycline has a protective effect on myocardial cell injury model. Studies have shown that Minocycline can protect neurons from DNA damage through inhibiting PARP-1 [17]. But whether Minocycline can protect myocardial cells after myocardial infarction by inhibiting PARP-1 is not clear, so this study aimed to establish the rat model of myocardial infarction, so as to study whether Minocycline could reduce the apoptosis, alleviate the inflammation, thereby protecting the myocardial cells after myocardial infarction, improving the myocardial remodeling and improving cardiac function through inhibiting the PARP-1 activity.