Long-term oral Asperosaponin VI attenuates cardiac dysfunction, myocardial fibrosis in a rat model of chronic myocardial infarction

Abstract

The aim of the study was to determine the effects of Asperosaponin VI (ASA VI), a triterpene saponin isolated from Dipsacus asper Wall, on chronic myocardial infarction (MI) and possible mechanisms in rats. MI was induced by permanent ligation of the left coronary artery. Twenty-four hours after MI, the rats were administered the extract by gavage (once a day). Six weeks after MI/sham surgery, cardiac dysfunction, infarct size (IS), cardiac fibrosis, hydroxyproline concentration, the oxidative stress parameter and inflammation mediators were examined. The results indicated that ASA VI improved left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), ±dP/dt, heart weight/body weight, right ventricular weight/body weight and lung weight/body weight (P < 0.01, P < 0.05). These were accompanied by the attenuation of cardiac fibrosis, IS and hydroxyproline concentration (P < 0.01, P < 0.05). ASA VI could decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), but increase IL-10 content (P < 0.01, P < 0.05). Furthermore, it also could raise the activities of catalase, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but reduce malonyldialdehyde (MDA) level (P < 0.01, P < 0.05). The results indicated that ASA VI improved cardiac function and myocardial fibrosis from myocardial ischemia injury, and this cardioprotection might be attributed to reduce oxidative stress and regulate inflammation mediators.

Introduction

As congestive heart failure (CHF) remains a fatal disease, the development of agents effective against this condition is urgently needed. CHF is a syndrome which represents the end-stage in the progression of cardiac hypertrophy caused by hypertension or valvular heart disease, or the progression of ischemic heart diseases such as angina pectoris and myocardial infarction (MI) (Wada et al., 2005). In recent years, researchers have found that many herbal medicines provide antioxidant effects on ischemic heart diseases and CHF (Sun et al., 2002, Ji et al., 2003). The degree of oxidative stress and the severity of the subsequent myocardial damage may depend on the imbalance between excessive production of reactive oxygen species (ROS) and the antioxidant defense within the heart (Hagen et al., 2009). The cardiovascular system is continuously exposed to both reactive oxygen and nitrogen species. Oxygen, although essential for tissue survival, can be injurious during ischemic myocardium (Zweier and Hassan Talukder, 2006). These injurious molecules create and exacerbate inflammation and oxidative stress, which lead to direct vascular remodeling, atherosclerosis, and autonomic dysfunction. Furthermore, ROS also stimulate signal transduction to elaborate inflammatory cytokines, e.g. tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in the ischemic region and surrounding myocardium as a host reaction. It is becoming increasingly apparent that inflammatory mediators play a crucial role in the development of heart failure, and several strategies to counterbalance different aspects of the inflammatory response are considered (Stefan et al., 2004). Moreover, increase in inflammatory cytokines, such as TNF-α and IL-6, as well as an increase in the production of hydroxyl radical, was observed in patients post-MI (Tavares et al., 2010). Based on these observations, it has been hypothesized that inhibiting high-output IL-6 and TNF-α production, and reducing oxidative stress in surrounding myocardium, can serve as the basis for the potential development of drugs for ischemic heart diseases and CHF.

Dipsacus asper (Xuduan) Wall, belongs to Dipsacaceae, is a perennial herb growing in the moist fields and mountains. The extract of D. asper can enhance the antioxidant status of blood and liver in rodents (Wong et al., 1996), and inhibit inflammatory reaction in animal models (Wang et al., 1996), which may contribute to its use in ischemic heart disease. Our findings also showed that ASA VI {3-O-[A-l-rhamnopyranosyl(1 → 2)-a-l-α-binopranosyl]hederagenin} (Fig. 1), a triterpene saponin isolated from D. asper Wall, provided significant cardioprotective effects against acute MI in rats via intravenous administration (Li et al., 2010). However, little is known about its myocardial preservation after chronic infarction by long-term oral. The aim of the study was to determine the effects of ASA VI on chronic MI in rats and the possible mechanisms involved. Importantly, this study provided evidence for the potent and highly efficacious effect of ASA VI as a cardioprotective agent for the potential intervention against chronic MI.