Cyclophilin A induces macrophage apoptosis and enhances atherosclerotic lesions in high‐fat diet‐fed hyperglycemic rabbits

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.