Abstract
Madagascine (3-isopentenyloxyemodin) can be chemically synthesized or purified from several Rhamnus species, and it is found to have more potent biological activities than the parent compound emodin. The aim of this study is to characterize the vasodilatory effect of madagascine on vasoconstriction and sphingosylphosphorylcholine induced vasospasm in ex vivo and reveal the potential mechanisms in vitro. The effects of madagascine on vasoconstriction of rat mesenteric resistance arteries (MRAs) induced by K+, methoxamine, and endothelin-1 were, respectively, studied. The cholesterol-enriched porcine coronary vascular smooth muscle (VSM) strips were used to investigate the effects of madagascine on abnormal constriction induced by sphingosylphosphorylcholine (SPC) which has a pivotal role in vasospasm. The vasodilatory effect was induced by madagascine (0.3–100 μM) in isolated rat MRAs and the vasodilatory effect was blocked by NO synthase inhibitor L-NAME and AMPK inhibitor compound C. Madagascine (10 μM) also significantly relaxed the abnormal constriction in porcine VSM induced by SPC and the effect was abolished by compound C. Madagascine significantly increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in endothelial cells while decreasing the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in VSM cells. Madagascine-induced vasodilatation was abrogated using small interfering RNA knockdown of AMPK. In summary, madagascine exerted vasodilatation through activating AMPK, leading to the activation of eNOS in endothelium and inhibition of ROCK/MYPT1 in VSM. This study suggests the potential value of madagascine in amelioration of vasospasm related cardiovascular diseases.
Highlights
Vascular vasodilatation is beneficial for amelioration of cardiovascular diseases including essentialand renal-parenchymal-disease-related hypertension, vascular remodeling, cardiac infarction, and congestive heart failure (Hisham and Bayraktutan, 2012; Kumar et al, 2012; Machino et al, 2014)
In mesenteric resistance arteries (MRAs) with an intact endothelium, madagascine exerted vasodilatation effect was significantly blocked by NO synthase inhibitor L-NAME and AMPK inhibitor compound C, respectively. These results suggest that AMPK/endothelial nitric oxide synthase (eNOS) signaling pathway is involved in madagascine-induced vasodilatation (Figure 4)
The phosphorylation of eNOS in human umbilical vein endothelial cells (HUVECs) was significantly increased and the phosphorylation of myosin phosphatase target subunit 1 (MYPT1) in human coronary artery smooth muscle cells (HCASMCs) cells was significantly decreased by madagascine
Summary
Vascular vasodilatation is beneficial for amelioration of cardiovascular diseases including essentialand renal-parenchymal-disease-related hypertension, vascular remodeling, cardiac infarction, and congestive heart failure (Hisham and Bayraktutan, 2012; Kumar et al, 2012; Machino et al, 2014). The activation of AMPK leads to vasodilatation through the phosphorylation of epithelial nitric oxide synthase (eNOS) at site Ser1177 in epithelium and a direct inhibition of vascular smooth muscle (VSM) constriction (Reihill et al, 2007; Bradley et al, 2010; Shuangxi et al, 2011). Smooth muscle constriction is induced by phosphorylation of 20-kDa myosin light chain (MLC), which is regulated by both Ca2+ dependent and Ca2+ independent mechanisms (Somlyo and Somlyo, 1994). AMPK activation leads to inhibition of Rho-associated protein kinase (ROCK) which mediates Ca2+ independent VSM constriction by inhibiting myosin phosphatase via phosphorylation of myosin phosphatase target subunit 1 (MYPT1) (Somlyo, 2002; Shuangxi et al, 2011). The relationship and between AMPK activation and SPC induced vasospasm remains unknown
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