Danqi soft capsule prevents infarct border zone remodelling and reduces susceptibility to ventricular arrhythmias in post‐myocardial infarction rats

Abstract

Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng ; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post‐myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post‐MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post‐MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α‐smooth muscle actin (α‐SMA), transforming growth factor‐β1 (TGF‐β1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF‐β1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post‐MI period.

Overview of Salvia miltiorrhiza as a Potential Therapeutic Agent for Various Diseases: An Update on Efficacy and Mechanisms of Action

“…For example, S. miltiorrhiza extract administration dose-dependently decreased the expression of COL I and COL III as assessed by immunohistochemistry and reduced areas of fibrotic heart tissue as observed with Masson’s stain [ 49 ]. Two studies further examined the effect of S. miltiorrhiza extract on the expression levels of the profibrotic cytokine TGF-β, which is a major mediator implicated in fibrotic remodeling of the heart and is thought to drive fibroblast-myofibroblast differentiation [ 117 ]; in both studies, down-regulation of TGF-β expression was observed, but different mechanisms were proposed regarding the anti-fibrotic effects of S. miltiorrhiza extract [ 49 , 55 ].…”

“…Besides, DQP administration up-regulated PPARα-RXR pathway, as shown by the increased protein expression of PPARα and RXRs as well as the decreased protein expression of NR2C2. Ma et al demonstrated that Danqi soft capsule (DQ), which was prepared from powdered water extracts of S. miltiorrhiza and Panax notoginseng , could inhibit infarct border zone (IBZ) remodeling and reduce susceptibility to ventricular tachyarrhythmias (VT) possibly via TGF-β 1 /Smad3 pathway in a rat model of post-myocardial infarction [ 55 ]. Oral administration of DQ at doses of 0.6, 0.9, or 1.2 g/kg for 4 weeks inhibited cardiac fibrosis in the IBZ as shown by the reduction in COL I and COL III expression levels; reversed Cx43 expression and distribution in the IBZ as assessed by Western blot and immunohistochemical staining; and prevented MI-induced myocyte hypertrophy in the IBZ as evidenced by the decreased mRNA expression levels of the hypertrophic marker atrial natriuretic peptide (ANP).…”

Cellular and Molecular Mechanism of Traditional Chinese Medicine on Ventricular Remodeling

“…(Chishao), Ligusticum chuanxiong (Chuanxiong), Prunus persica (L.) Batsch (Taoren), Carthamus tinctorius L. (Honghua), and Lumbricus (Dilong), can inhibit the activation of Smad3 and Smad4, which then inhibit the transcription of pro-fibrotic molecules, including the transcription of α-smooth muscle actin, collagen, and tissue inhibitors of MMPs, and finally, reduce the activation of myofibroblasts and matrix deposition, leading to the alleviation of pressure overload-induced cardiac remodeling (81). Dan-Qi soft capsules, Tong-Guan capsules, and Qi-Li-Qiang-Xin can inhibit the differentiation and formation of myofibroblasts by inhibiting the TGF-β1/Smad3 pathway, having an effect of inhibiting VR (32,82,83). Moreover, Qi-Li-Qiang-Xin may also promote the TGF-β3/Smad7 signal pathway to play an anti-VR effect (84).…”

Advances of Traditional Chinese Medicine Regulating Connexin43 in the Prevention and Treatment of Myocardial Infarction

“…Shengmai injection and Xuesaitong injection can increase the threshold of ventricular fibrillation in rats with MI, and the mechanism of action is related to improving cardiac structure and Cx43 expression after MI [ 60 ]. Tongguan capsules and Dan Qi soft capsules can increase Cx43 expression, intervene in interstitial fibrosis and cardiomyocyte hypertrophy, reduce left-ventricular remodeling and dysfunction, and reduce the occurrence of arrhythmia [ 61 , 62 ]. Cx43 is related to different biological processes, so the prescription for enriching qi and activating blood may also regulate the concentration of free Ca 2+ in cardiomyocytes, improve the GJ communication between cells, repair the cytoskeleton and ultrastructure of cardiomyocytes, and thus, upregulate the expression of Cx43 protein and protect cardiomyocytes.…”