A metabolite of Danshen formulae attenuates cardiac fibrosis induced by isoprenaline, via a NOX2/ROS/p38 pathway

Abstract

BACKGROUND AND PURPOSECardiac fibrosis is a common feature of advanced coronary heart disease and is characteristic of heart disease. However, currently available drugs against cardiac fibrosis are still very limited. Here, we have assessed the role of isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxylpropanoate (IDHP), a new metabolite of Danshen Dripping Pills, in cardiac fibrosis mediated by the β-adrenoceptor agonist, isoprenaline, and its underlying mechanisms. EXPERIMENTAL APPROACHIdentification of IDHP was identified by mass spectrometry, and proton and carbon nuclear magnetic resonance spectra. Myocardial collagen was quantitatively assessed with Picrosirius Red staining. Expression of mRNA for collagen was evaluated with real-time PCR. Phosphorylated and total p38 MAPK, NADPH oxidase (NOX) and superoxide dismutase (SOD) were analysed by Western blot. Generation of reactive oxygen species (ROS) generation was evaluated by dihydroethidium (DHE) fluorescent staining. NOX2 was knocked down using specific siRNA. KEY RESULTSIDHP attenuated β-adrenoceptor mediated cardiac fibrosis in vivo and inhibited isoprenaline-induced proliferation of neonatal rat cardiac fibroblasts (NRCFs) and collagen I synthesis in vitro. Phosphorylation of p38 MAPK, which is an important mediator in the pathogenesis of isoprenaline-induced cardiac fibrosis, was inhibited by IDHP. This inhibition of phospho-p38 by IDHP was dependent on decreased generation of ROS. These effects of IDHP were abolished in NRCFs treated with siRNA for NOX2. CONCLUSIONS AND IMPLICATIONSIDHP attenuated the cardiac fibrosis induced by isoprenaline through a NOX2/ROS/p38 pathway. These novel findings suggest that IDHP is a potential pharmacological candidate for the treatment of cardiac fibrosis, induced by β-adrenoceptor agonists.

Role of phosphodiesterase 4 expression in the Epac1 signaling-dependent skeletal muscle hypertrophic action of clenbuterol

“…Unlike other adrenergic agents such as isoproterenol (a nonselective b-AR agonist) (Yin et al 2015), pharmacological stimulation of b 2 -AR with CB induces hypertrophy of TA (fast-twitch), masseter muscle (fast-twitch), and cardiac muscle, but not SOL (slow-twitch) in WT, without causing an increase in interstitial collagen (fibrosis) as shown in this study (Fig. 2) and previously by other groups (Wong et al 1997(Wong et al , 1998Zeman et al 2000), even though mice with a very high level of overexpression of b 2 -AR develop fibrosis (Liggett et al 2000).…”

Identification of metabolites of isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxypropanoate in rats by high‐performance liquid chromatography combined with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry

“…A novel compound, isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxypropanoate (IDHP), was found to be a bioactive metabolite of Danshen during the research process of CDDP metabolism in vivo (Pei et al ., ; Wang et al ., 2011a; Zheng et al ., ). Our previous pharmacological study showed that IDHP possesses a variety of biological activities such as anti‐myocardial and anti‐cerebral ischemia (Cheng et al ., ; Tian et al ., ), anti‐hypoxia (Xiong et al ., ), anti‐arrhythmic (Wang et al ., ), anti‐myocardial fibrosis (Lu et al ., ; Yin et al ., ), anti‐oxidant (Cheng et al ., 2011), anti‐inflammation (Wang et al ., ) and vasodilative effects (Li et al ., ; Wang et al ., ). These remarkable activities give IDHP the potential to become a promising new drug for fighting diseases in the cardio‐cerebrovascular system.…”

Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris

“…The pharmacologically active ingredients of a phytocomplex such as TCM compound formulations ( fufang ) are not always the original natural molecules but may be their host‐specific metabolites or molecular complexes formed following co‐administration of selected herbs. We have previously discovered an active Dantonic metabolite (isopropyl 3‐(3,4‐dihydroxyphenyl)‐2‐hydroxy‐propanoate, IDHP) and found it was a NO‐independent vasodilator, which attenuated cardiac fibrosis in rats as well (Zheng, Zhao, Zhao, et al, ; Yin et al, ). Tanshinol (DSS, (+) β‐(3,4‐dihydroxyphenyl) lactic acid) is the primary ingredient in an aqueous extract of S. miltiorrhiza and exhibits pleiotropic activities, such as protection of vascular endothelial cells against homocysteine (Hcy)‐induced damage (Chan et al, ) and protection of myocardium from ischaemia/reperfusion injury (Yang et al, ).…”