A novel Ca2+ current blocker promotes angiogenesis and cardiac healing after experimental myocardial infarction in mice.

We previously reported a novel danshensu derivative (R)-(3,5,6-Trimethylpyrazinyl) methyl-2-acetoxy-3-(3,4-diacetoxyphenyl) propanoate (ADTM) that exhibited promising cardiovascular protective activities, such as antioxidant and antiplatelet activities, as well as arterial relaxation. Particularly, ADTM treatment for 24 h exhibited anti-oxidative activity and effectively protected against acute myocardial infarction (MI) in a rat model. Here, we further investigated the pharmacological actions of 14 days of treatment with ADTM in alleviating and restoring the MI size by stimulating revascularization. The pro-angiogenesis activity of ADTM has been validated in multiple experimental models including MI mouse, zebrafish, human umbilical vein endothelial cells (HUVECs) and A7r5 vascular smooth muscle cells (VSMCs). In addition, the effect of ADTM on L-type Ca2+ current (ICaL) was determined. We demonstrated that ADTM (12-24 mg/kg) treatment for 14 days significantly decreased myocardial infarct size, increased the blood vessel density compared to vehicle in the myocardial peri-infarct area, and ADTM (24 mg/kg) enhanced the serum VEGF level in MI mice (P < 0.05). We also demonstrated that treatment with ADTM at 50-200 µM rescued chemical-induced blood vessel loss in zebrafish. Although ADTM did not directly promote the features of angiogenesis in HUVECs, ADTM significantly increased VEGF production in a dose-dependent manner in A7r5 cells (P < 0.05). A patch clamp experiment demonstrated that ADTM (200 µM) inhibited ICaL at all depolarizing voltages, with > 50% inhibition at + 10 mV. Taken together, our results indicated that ADTM served as a Ca2+ current blocker, promoted angiogenesis and reduced experimental myocardial infarct size in mice, probably through stimulation of VEGF production in VSMCs.

A novel Danshensu derivative confers cardioprotection via PI3K/Akt and Nrf2 pathways.

BACKGROUND: Danshensu (3-(3,4-dihydroxyphenyl) lactic acid, DSS) is one of the most promising cardioprotective components in the root of Salvia miltiorrhiza but its poor chemical stability poses hurdles in its therapeutic development. It is therefore desirable to enhance the stability of DSS by chemical modification to improve its activities. In the present study, a novel DSS derivative named ADTM was synthesized and characterized for its cardioprotective properties. METHODS: Oxidative stress was induced in H9c2 cardiomyoblast cells by tert-butylhydroperoxide (t-BHP) and the protective effects of ADTM were evaluated. For in vivo study, adult rats were treated with vehicle, DSS, ADTM or amlodipine (n=6-8/group) for 24h before the induction of acute myocardial ischemia. At the end of each experiment, infarct size was measured. Underlying the mechanisms of the cardioprotective effects of ADTM were further investigated in H9c2 cells and rat myocardium by evaluating the effects of Nrf2 (NF-E2-related factor 2) and Akt/PI3K pathways. RESULTS: ADTM was approximately 10 times more effective than DSS against t-BHP-induced cell injury in H9c2 cells. In rat myocardial ischemia model, ADTM treatment significantly alleviated myocardial infarction. Akt/PI3K and Nrf2 pathways were demonstrated to be involved in both in vitro and in vivo experiments. CONCLUSIONS: These results demonstrated that ADTM displayed much better cardioprotective effects than its parent compounds both in vitro and in vivo. This cardioprotection is mediated, at least in part, through Akt/PI3K and Nrf2 pathways. This novel compound represents a promising candidate for the treatment of cardiovascular diseases (CVDs), particularly myocardial infarction.