Melatonin Attenuates Aortic Endothelial Permeability and Arteriosclerosis in Streptozotocin-Induced Diabetic Rats

Abstract

The development of diabetic macrovascular complications is a multifactorial process, and melatonin may possess cardiovascular protective properties. This study was designed to evaluate whether melatonin attenuates arteriosclerosis and endothelial permeability by suppressing the myosin light-chain kinase (MLCK)/myosin light-chain phosphorylation (p-MLC) system via the mitogen-activated protein kinase (MAPK) signaling pathway or by suppressing the myosin phosphatase-targeting subunit phosphorylation (p-MYPT)/p-MLC system in diabetes mellitus (DM). Rats were randomly divided into 4 groups, including control, high-fat diet, DM, and DM + melatonin groups. Melatonin was administered (10 mg/kg/d) by gavage for 12 weeks. The DM significantly increased the serum fasting blood glucose and lipid levels, as well as insulin resistance and endothelial dysfunction, which were attenuated by melatonin therapy to various extents. Importantly, the aortic endothelial permeability was significantly increased in DM rats but was dramatically reversed following treatment with melatonin. Our findings further indicated that hyperglycemia and hyperlipidemia enhanced the expressions of MLCK, p-MYPT, and p-MLC, which were partly associated with decreased membrane type 1 expression, increased extracellular signal-regulated kinase (ERK) phosphorylation, and increased p38 expression. However, these changes in protein expression were also significantly reversed by melatonin. Thus, our results are the first to demonstrate that the endothelial hyperpermeability induced by DM is associated with increased expressions of MLCK, p-MYPT, and p-MLC, which can be attenuated by melatonin at least partly through the ERK/p38 signaling pathway.

Sitagliptin inhibits endothelin-1 expression in the aortic endothelium of rats with streptozotocin-induced diabetes by suppressing the nuclear factor-κB/IκBα system through the activation of AMP-activated protein kinase

“…Serum NO levels were measured using a commercial kit (Jiancheng, Nanjing, China). The insulin sensitivity index was calculated using the [1/(FBG × fasting insulin)] formula ( 18 ). All analyses were performed in duplicate.…”

Effects of melatonin on cardiovascular diseases: progress in the past year

“…In addition to MAPK signaling, a recent study showed that melatonin decreased aortic endothelial permeability and atherosclerosis in a mouse model of diabetes by decreasing the expression of myosin light chain kinase (MLCK), myosin phosphatase-targeting subunit phosphorylation, and myosin light-chain phosphorylation. Melatonin also decreased upstream expression of extracellular signal-related kinase (ERK) and p38 [ 51 ]. Zhu et al [ 52 ] found that micro ribonucleic acid-29b (miR-29b) promotes endothelial permeability and apoptosis in high-fat diet-fed apoE knock-out mice by down-regulating the expression of MT1, which is a melatonin receptor.…”

Pleiotropic Effects of Melatonin

“…[45] Later on, it was suggested that melatonin modulated the mitogen-activated protein kinase (MAPK) signal transduction pathway. Tang et al, in a study on diabetic mouse, demonstrated that melatonin reduced the aortic endothelial permeability and atherosclerosis following treatment with melatonin, [46] which could have resulted from the reduction of the expression of myosin light chain kinase (MLCK), myosin phosphatase [targeting subunit phosphorylation], and myosin light-chain phosphorylation acting via extracellular signal-related kinase (ERK/p38) signal transduction pathway.. [46] In another recent study which was conducted on high-fat diet fed rats and induced diabetic rats, melatonin was reported to reverse the endothelial function and vascular responses. [47] A double-blind, randomized, controlled trial study on 39 patients (32 men and 7 women) with three vessels coronary disease has revealed that melatonin have beneficial effects on endothelial oxidative stress even in patient with severe and advanced atherosclerosis.…”