Vinitha, Anandan and Santhosh Kumar, T R and Abdul, Jaleel and Thushara, Thulaseedharan and Pillai , M. R and Surya , Ramachandran (2021) Cyclophilin A induces macrophage apoptosis and enhances atherosclerotic lesions in high-fat diet-fed hyperglycemic rabbits. FASEB bioAdvances, 3 (5). pp. 305-322. ISSN 2573-9832

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Abstract

Macrophage apoptosis is a key contributor to the progression of atherosclerosis. Cyclophilin A, a monocyte secretory protein associated with the initiation of atherosclerosis has an inherent nuclease activity. This study reports the mechanism by which cyclophilin A causes apoptosis of macrophages and accelerates the progression of atherosclerosis. Aortic lesion formation and apoptosis were studied in New Zealand White rabbits (NZW) which were fed high-fat diet (HFD) for 12 weeks. Using monocytes and HFD-fed rabbits we demonstrate that cyclophilin A induces mitochondrial membrane potential loss and mitochondrial pore transition protein opening through caspase 3 activation. En face staining revealed a significant increase in the lesion area in HFD-fed rabbits. Levels of glucose, cholesterol and proinflammatory cytokines were higher in these animals compared to rabbits fed with a normal diet. In the aorta of HFD-fed rabbits, medial vascular smooth muscle cells were disorganized and there was a loss of integrity of the endothelium. An 8-fold increase was seen in the number of apoptotic cells in the lesion area of HFD-fed NZW rabbits which were associated with an elevation in plasma cyclophilin A levels. siRNA knockdown of cyclophilin A gene reduced activation of caspase 3 in macrophages. Treatment with cyclosporine A, an inhibitor of cyclophilin A, significantly attenuated apoptosis in macrophages. Our study indicates that inhibitors of proinflammatory cytokines such as cyclophilin A may arrest macrophage apoptosis and result in a regression of advanced atherosclerotic lesions.

Item Type:	Article
Uncontrolled Keywords:	MPTP; atherosclerosis; caspase 3; cyclophilin A; macrophage apoptosis.
Subjects:	Cancer Research Cardiovascular Diseases And Diabetes Biology
Depositing User:	Central Library RGCB
Date Deposited:	27 Jan 2022 07:35
Last Modified:	27 Jan 2022 07:35
URI:	http://rgcb.sciencecentral.in/id/eprint/1115

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