Abstract
Mitochondrial fission plays a role in cardiovascular calcification. Melatonin has previously been shown to protect against cardiovascular disease, so this study sought to explore whether it attenuates vascular calcification by regulating mitochondrial fission via the AMP‐activated protein kinase/dynamin‐related protein 1 (AMPK/Drp1) signalling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure the expression of runt‐related transcription factor 2 (Runx2), Drp1 and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were down‐regulated, Drp1 was reduced in response to melatonin, and this was accompanied by decreased apoptosis. Melatonin also reduced levels of mitochondrial superoxide, reversed β‐glycerophosphate (β‐GP)‐induced ΔΨm dissipation and decreased mitochondrial fragmentation. The effects of melatonin in β‐GP‐treated VSMCs were similar to those of mitochondrial division inhibitor 1. Melatonin significantly activated the expression of AMPK and decreased Drp1 expression. Treatment with compound C ablated the observed benefits of melatonin treatment. These findings indicate that melatonin protects VSMCs against calcification by inhibiting mitochondrial fission via the AMPK/Drp1 pathway.
Highlights
Vascular calcification (VC) is prevalent in coronary artery disease, and the extent of VC predicts cardiovascular risk.[1]
The present study aimed to investigate whether melatonin reduces vascular smooth muscle cells (VSMCs) calcification by inhibiting mitochondrial fission through the AMP-activated protein kinase (AMPK)/Drp[1] signalling pathway
Cleaved caspase 3 protein expression was decreased in the melatonin and Mdivi-1 groups (Figure 3F). These results indicate that melatonin protected VSMCs against apoptosis via mitochondrial fission inhibition
Summary
Vascular calcification (VC) is prevalent in coronary artery disease, and the extent of VC predicts cardiovascular risk.[1]. Mitochondrial fission plays a role in cardiovascular calcification, and its inhibition was reported to reduce osteogenic differentiation, matrix mineralization and type 1 collagen secretion.[6] Dynaminrelated protein 1 (Drp1) is a key regulator of mitochondrial fission, and the AMP-activated protein kinase (AMPK)/Drp[1] pathway is associated with mitochondrial fission during cardiovascular disease.[7,8] phosphate-AMPK protein levels were reported to decrease in VC, while ghrelin improved VC through AMPK activation,[9] and metformin inhibited β-glycerophosphate (β-GP)-induced impairment of mitochondrial biogenesis via AMPK activation in VC.[10]. The present study aimed to investigate whether melatonin reduces VSMC calcification by inhibiting mitochondrial fission through the AMPK/Drp[1] signalling pathway
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