Melatonin Attenuates Aortic Endothelial Permeability and Arteriosclerosis in Streptozotocin-Induced Diabetic Rats: Possible Role of MLCK- and MLCP-Dependent MLC Phosphorylation.

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.

• Authors: Song-tao Tang, Huan Su, Qiu Zhang, Hai-qin Tang, Chang-jiang Wang, Qing Zhou, Wei Wei, Hua-qing Zhu, Yuan Wang
• Journal: Journal of cardiovascular pharmacology and therapeutics (J Cardiovasc Pharmacol Ther) Vol. 21 Issue 1 Pg. 82-92 (Jan 2016) ISSN: 1940-4034 [Electronic] United States
• PMID: 25944844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015.

Chemical References

• Blood Glucose
• Lipids
• Myosin Light Chains
• Streptozocin
• Myosin-Light-Chain Kinase
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Myosin-Light-Chain Phosphatase
• Melatonin

Topics

• Animals
• Aorta, Abdominal (diagnostic imaging, drug effects, enzymology, physiopathology)
• Aortic Diseases (blood, chemically induced, enzymology, physiopathology, prevention & control)
• Arteriosclerosis (blood, chemically induced, enzymology, physiopathology, prevention & control)
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (blood, chemically induced, drug therapy, enzymology, physiopathology)
• Diabetic Angiopathies (blood, chemically induced, enzymology, physiopathology, prevention & control)
• Endothelium, Vascular (diagnostic imaging, drug effects, enzymology, physiopathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Lipids (blood)
• Male
• Melatonin (pharmacology)
• Myosin Light Chains (metabolism)
• Myosin-Light-Chain Kinase (metabolism)
• Myosin-Light-Chain Phosphatase (metabolism)
• Permeability
• Phosphorylation
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Streptozocin
• Time Factors
• Ultrasonography
• p38 Mitogen-Activated Protein Kinases (metabolism)