Melatonin Attenuates Vascular Smooth Muscle Contraction Through the γ-Secretase/Notch Intracellular Domain/Myocardin Pathway.

ABSTRACT: Inositol 1, 4, 5-trisphosphate (IP3) signaling-mediated calcium release drives the contraction of vascular smooth muscles and hence regulates blood vessel volume and blood pressure. Melatonin supplementation has been suggested to be beneficial for hypertension. To determine whether the blood pressure-lowering effect of melatonin was accounted for by IP3 signaling, we evaluated the vasoconstriction response and IP3 signaling in isolated mouse thoracic aortic rings during melatonin incubation. C57BL/6 mice were given intraperitoneal injections daily with melatonin, and the systolic blood pressure and contractility of aortic rings from melatonin-treated mice were decreased, and the contraction suppression effect of melatonin was attributed to the impaired expression of contractile proteins in vascular smooth muscle cells rather than IP3 signaling. Our results further showed that melatonin increased the expression of γ-secretase, which could cleave and release the notch intracellular domain, and the notch intracellular domain prevented the transcription of contractile genes by interfering with the interaction between serum response factor and myocardin, the master regulator of contractile protein. In this article, we report a novel mechanism by which melatonin regulates smooth muscle contractility that does not depend on IP3 signaling.

Mechanism of Action of Acupotomy in Inhibiting Chondrocyte Apoptosis in Rabbits with KOA through the PI3K/Akt Signaling Pathway.

OBJECTIVE: We examined the effects of acupotomy on the PI3K/Akt signaling pathway to elucidate the mechanism of action of acupotomy on articular chondrocyte apoptosis among rabbits with knee osteoarthritis (KOA). METHODS: New Zealand rabbits were randomly assigned to a healthy control group, placebo group, acupotomy group, and drug group, with 10 rabbits in each group. Changes in chondrocytes were examined by hematoxylin and eosin staining, and articular chondrocyte apoptosis was measured by electron microscopy and immunofluorescence. The mRNA and protein expression levels of PI3K and Akt were measured by real-time quantitative PCR and Western blot. RESULTS: In contrast, less chromatin margination and clear and smooth nuclear envelope boundary were visible in the acupotomy group and drug group. The number of apoptotic chondrocytes in the knee joint of rabbits was significantly higher in the placebo group than that in the acupotomy group and drug group (P < 0.05). The acupotomy group had a nonsignificantly lower number of apoptotic chondrocytes than the drug group (P > 0.05). Furthermore, the mRNA and protein expression levels of PI3K and Akt were significantly higher in the acupotomy group and drug group than those in the placebo group (P < 0.05) and were closer to normal levels in the acupotomy group than those in the drug group (P < 0.05). PI3K and Akt expression levels were negatively correlated with chondrocyte apoptosis in the knee joint of rabbits in all groups. CONCLUSION: Inhibiting chondrocyte apoptosis in the knee joint of KOA rabbits by upregulating the PI3K/Akt signaling pathway may be a possible mechanism of acupotomy in treating KOA.