Key result
Serpina3c deficiency in Apoe-/- mice exacerbated atherosclerosis and increased VSMC and macrophage numbers in aortic plaques, highlighting its protective role as a novel thrombin inhibitor.
Why the study?
Abnormal vascular smooth muscle cell proliferation is critical in atherosclerosis, and the role and mechanisms of serpina3c in atherosclerosis and VSMC proliferation regulation remained to be investigated.
Serpina3c protects against atherosclerosis by acting as a novel thrombin inhibitor, negatively regulating VSMC proliferation via the thrombin/PAR-1 system and ERK1/2 and JNK signaling.
Highlights Serpina3c as potential atherosclerosis target; leaves open human relevance and therapeutic translation.
Abnormal vascular smooth muscle cell (VSMC) proliferation is a critical step in the development of atherosclerosis. Serpina3c is a serine protease inhibitor (serpin) that plays a key role in metabolic diseases. The present study aimed to investigate the role of serpina3c in atherosclerosis and regulation of VSMC proliferation and possible mechanisms. Serpina3c is down-regulated during high-fat diet (HFD)-induced atherosclerosis. An Apoe-/-/serpina3c-/--double-knockout mouse model was used to determine the role of serpina3c in atherosclerosis after HFD for 12 weeks. Compared with Apoe-/- mice, the Apoe-/-/serpina3c-/- mice developed more severe atherosclerosis, and the number of VSMCs and macrophages in aortic plaques was significantly increased. The present study revealed serpina3c as a novel thrombin inhibitor that suppressed thrombin activity. In circulating plasma, thrombin activity was high in the Apoe-/-/serpina3c-/- mice, compared with Apoe-/- mice. Immunofluorescence staining showed thrombin and serpina3c colocalization in the liver and aortic cusp. In addition, inhibition of thrombin by dabigatran in serpina3c-/- mice reduced neointima lesion formation due to partial carotid artery ligation. Moreover, an in vitro study confirmed that thrombin activity was also decreased by serpina3c protein, supernatant and cell lysate that overexpressed serpina3c. The results of experiments showed that serpina3c negatively regulated VSMC proliferation in culture. The possible mechanism may involve serpina3c inhibition of ERK1/2 and JNK signaling in thrombin/PAR-1 system-mediated VSMC proliferation. Our results highlight a protective role for serpina3c as a novel thrombin inhibitor in the development of atherosclerosis, with serpina3c conferring protection through the thrombin/PAR-1 system to negatively regulate VSMC proliferation through ERK1/2 and JNK signaling.
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Qian et al. (2021) studied Atherosclerosis. serpina3c knockout vs. Apoe-/- mice was evaluated on Atherosclerosis severity and number of VSMCs and macrophages in aortic plaques. Serpina3c deficiency in Apoe-/- mice exacerbated atherosclerosis and increased VSMC and macrophage numbers in aortic plaques, highlighting its protective role as a novel thrombin inhibitor.
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