Danshensu Inhibits β-Adrenergic Receptors-Mediated Cardiac Fibrosis by ROS/p38 MAPK Axis

Abstract

Danshensu, the effective ingredient of the plant Salvia miltiorrhiza (Danshen), has been widely used for treatment of cardiovascular diseases. Cardiac fibrosis is an important process in pathological cardiac remodeling and leads to heart failure. We investigated the effect of Danshensu on β-adrenergic receptor (β-AR)-mediated cardiac fibrosis and the involved signaling transduction. Danshensu inhibited cardiofibroblast proliferation and collagen I synthesis induced by isoproterenol (ISO), a selective β-AR agonist. Phosphorylation of p38 mitogen-activated protein kinase (MAPK), which mediates ISO-induced cardiac fibrosis, was negatively regulated in this process. The negative regulation depended on the ISO inhibition of reactive oxygen species (ROS) production. Taken together, Danshensu may inhibit β-AR-mediated cardiac fibrosis by negative regulation of ROS-p38 MAPK signaling.Key words Danshensu; β-adrenergic receptor; cardiac fibrosis; p38 MAPK; reactive oxygen specy Cardiac fibrosis is a pivotal phenomenon in pathological cardiac remodeling and is a hallmark of heart diseases. It is characterized by excessive extracellular matrix accumulation and fibroblast deposition and eventually destroys the organ architecture and abolishes normal function.1-3) Myocardial fibrosis is a major biological determinant of fatal events in cardiac remodeling, including heart failure, severe arrhythmias and sudden cardiac death.4,5) Cardiac fibrosis can be caused by various factors, such as the chronic activation of the sympathetic nervous system, myocardial hypoxia, ischemia, senescence, inflammation and hormones. β-Adrenergic receptors (β-ARs) and their associated guanine nucleotide regulatory protein (G protein)/adenylyl cyclase signal transduction pathways, are central to the regulation of cardiac function. Continuous activation of β-ARs plays an important role in cardiac dysfunction.6-8) Cardiac function was altered in β 1 -AR transgenic mice with cardiac hypertrophy, which could be inhibited by β-AR blockers.8) Consecutive administration with isoproterenol (ISO), a β-AR agonist, caused cardiac fibrosis in rats. 9,10) p38 mitogen-activated protein kinase (p38 MAPK) and reactive oxygen species (ROS) play a critical role in cardiac * To whom correspondence should be addressed. e-mail: lizijian@bjmu.edu.cn;zhengxh@nwu.edu.cnThe authors declare no conflict of interest. # These authors contributed equally to this work.

Aspirin alleviates cardiac fibrosis in mice by inhibiting autophagy

“…In this study, we found that ASA performed its anti-fibrotic function at least partly It has been reported that an increase in ROS levels is accompanied by p38 activation, fibrosis, apoptosis and cardiac dys- [18,30] . In this study, ASA inhibited levels of ROS and phosphorylated p38 when inhibiting fibrosis and apoptosis.…”

“…The function of ROS in ASA-mediated inhibition of CF pro liferation and apoptosis Many ASA functions have been associated with inhibited ROS [17,18] . Here, our data showed that ASA inhibited ROS in CFs ( Figure 6A).…”

“…The pathogenesis of cardiac fibrosis is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs) and the activation and migration of cardiac fibroblasts (CF) [17,18] . Furthermore, many reports suggest that ROS and the p38 axis play important roles in cardiac fibrosis [18] . Whether and how ROS participate in ASA-induced antifibrosis processes still requires clarification.…”

Danshensu protects against ischemia/reperfusion injury and inhibits the apoptosis of H9c2 cells by reducing the calcium overload through the p-JNK-NF-κB-TRPC6 pathway

“…Previous studies have confirmed that DSS has biological activities in that it improves microcirculation and exerts cardiovascular protective effects. For example, DSS has been shown to restore endothelium-dependent vasorelaxation via the prostacyclin pathway by increasing cyclooxygenase (COX)-2 gene expression and prostacyclin production (25), and thus it suppresses the formation of reactive oxygen species (ROS) and protects the myocardium against ischemia (26), protecting endothelial cells against injury induced by inflammation and inhibiting apoptosis (27,28), as well as inhibiting cardiac fibrosis through the negative regulation of ROS-/p38 MAPK signaling (29).…”

Neuroprotective effect and underlying mechanism of sodium danshensu [3-(3,4-dihydroxyphenyl) lactic acid from Radix and Rhizoma Salviae miltiorrhizae = Danshen] against cerebral ischemia and reperfusion injury in rats

“…It has been demonstrated that DSS is an excellent candidate for removing blood stasis, improving microcirculation and preventing platelet from adhesion and aggregation (Lu et al 2014). In addition, single or repeated dose toxicity studies suggested that DSS does not cause any signs of toxicity ).…”