No abstract

Background Cardiac dysfunction and remodeling are serious complications of sepsis and are correlated with high mortality. RCAN1 is a feedback regulator of cardiac hypertrophy. Here we aim to investigate role of RCAN1 in septic cardiomyopathy. Methods RCAN1-/- mice and WT mice were randomly divided into control and LPS-induced groups, some with Midiv-1 or KN93 treatment. The protein levels of RCAN1, p-ERK1/2, NFAT3, Drp1, p-Drp1, p-CaMKII in cardiac tissue or cultured cardiomyocytes were detected by Western blotting. Myocardial function was assessed by echocardiography. Cardiac hypertrophy and fibrosis were detected by H&E and Masson's trichrome staining. Mitochondrial morphology was examined by transmission electron microscope. Serum level of LDH was detected by ELISA. Results Our data showed that RCAN1 was downregulated in septic mouse heart and LPS-induced cardiomyocytes, and RCAN1-/- mice had impaired cardiac function and severe myocardial hypertrophy and fibrosis. NFAT3 and p-ERK1/2 were significantly increased in heart tissue of RCAN1-/- mice. Further, RCAN1 deficiency aggravated sepsis-induced cardiac mitochondrial injury as indicated by increased ROS production, pathological fission and the loss of mitochondrial membrane potential. Inhibition of fission by Mdivi-1 reversed LPS-induced cardiac hypertrophy, fibrosis and dysfunction in RCAN1-/- mice. Moreover, RCAN1 depletion caused mitochondrial translocation of CaMKII, which promoted fission and septic hypertrophy. Inhibition of CaMKII with KN93 reduced excessive fission, improved LPS-induced cardiac remodeling and dysfunction in RCAN1-/- mice. Conclusions Our finding demonstrated that RCAN1 deficiency aggravated mitochondrial injury and septic cardiomyopathy through activating CaMKII. RCAN1 serves as a novel therapeutic target for treatment of sepsis-related cardiac remodeling and dysfunction.