Abstract
p21 has emerged as an important protein involved in cardiovascular diseases, but its role remains controversial. Recently, p21 has been reported to mediate inflammatory responses. As inflammatory responses are a feature of sepsis, our study investigated whether p21 has a role in cardiac dysfunction induced by sepsis and analyzed the mechanisms involved. To establish a mouse sepsis model, p21 global knockout (p21KO) and C57BL/6J wild-type (WT) male mice were treated with 5 mg/kg LPS intraperitoneally for 6, 24, or 48 h. After LPS stimulation, the level of p21 had significantly increased in the WT mice and in cardiomyocytes. Cardiac dysfunction induced by LPS was markedly aggravated in p21KO mice relative to that of WT mice. Downregulation of p21 expression exacerbated the LPS-mediated inflammatory response, and it increased oxidative stress as well as mitochondrial damage in the heart and in cardiomyocytes. In contrast, overexpressing p21 attenuated the increase of TNFα and promoted the increase of SOD2. Moreover, p21 regulated the LPS-induced autophagy activation; that is, the increase in autophagy was impaired when p21 expression was decreased, whereas the increase was significant when p21 was overexpressed. The autophagy inducer rapamycin partially rescued the cardiac deterioration caused by p21 downregulation in the LPS-stimulated groups. In addition, p21 regulated the autophagy level by interacting with LC3B. These results revealed that p21 controls LPS-induced cardiac dysfunction by modulating inflammatory and oxidative stress, and it is partially dependent on regulating the autophagy level. This study is the first to show that p21 could interact with LC3B to promote autophagy for the improvement of cardiac function during sepsis.