1642: The Cardiac Protective Role of Vav3 in Septic Cardiomyopathy via Modulating Calcium Homeostasis

Introduction: Septic cardiomyopathy (SIC) was a severe organ dysfunction associated with sepsis. Previous studies have found that Vav Guanine Nucleotide Exchange Factor 3 (Vav3), a Rho GTPase regulated by tyrosine phosphorylation, mediated Lipopolysaccharide (LPS)-induced macrophage migration. However, the role of Vav3 in septic cardiomyopathy remains unclear. Therefore, this study aimed to investigate the role and mechanism of Vav3 in septic cardiomyopathy. Methods: First, single-cell transcriptomics in a cecal ligation and puncture rat model (CLP) was used to detect the expression and cellular localization of Vav3 in cardiac tissue. qPCR, western blot, and immunofluorescence staining were utilized to verify the RNA and protein expression levels. Echocardiography was used to measure cardiac function. And the visual edge detection system was utilized to observe the systolic/diastolic function of cardiomyocytes. Results: Our result revealed that Vav3 was reduced in CLP rat cardiomyocytes via single-cell transcriptomics. We further verified that Vav3 had decreased expression similarity and colocalization within cardiomyocytes in the heart tissue of CLP and LPS models. In vitro, Vav3 also declined in the LPS group. After cardiomyocyte-specific elevation of Vav3, the mortality rate was significantly reduced. In addition, cardiac function was reversed notably, including ejection fraction, fractional shortening rate, and E/e’ index. The serum level of BNP and cTnT levels were significantly downregulated. Further extraction of primary cardiomyocytes, we revealed that the average and peak velocities of contraction/relaxation increased in the LPS group. The intracytoplasmic Ca2+ concentration rose significantly, and calcium transients deteriorated. We also observed that the expression level of pRho/Rho, serum response factor (SRF), and Sarco/endoplasmic reticulum calcium ATPase (SERCA) was increased with the elevation of Vav3 in the LPS group. Meanwhile, the intranuclear proportion of SRF was raised. Conclusions: Vav3 was a protective factor against death and cardiac dysfunction in SIC. Vav3 may regulate cardiomyocyte calcium homeostasis to impair cardiomyocyte systolic/diastolic dysfunction through the Rho-SRF-SERCA axis in SIC.