Abstract P2039: The Absence Of Sigmar1 Causes Increased Protein Aggregation And Aggravated Cardiac Dysfunction In R120g- αb-Crystallin Mouse

Background: αB-Crystallin (CryAB) is a molecular chaperone responsible for protecting intermediate filaments by maintaining the structural integrity of the sarcomere. Mutation in CryAB at Arg120Gly (CryAB R120G ) causes the formation of toxic pre-amyloid oligomers and protein aggregation, contributing to cardiac dysfunction. In the event of proteotoxic insult, the chaperone proteins function to prevent the accumulation of protein aggregates. One of the multitasking chaperone proteins abundantly expressed in the heart and known to have molecular roles in the clearance of misfolded protein aggregates is Sigmar1. However, Sigmar1’s role in cardiac proteotoxicity and protein aggregation remains unknown. Hypothesis: We hypothesize that Sigmar1 plays a protective role in the degradation of protein aggregates in the heart. Here, we investigated the functional role of Sigmar1 in misfolded proteins aggregation-induced pathological cardiac remodeling and heart failure in CryAB R120G mice. Methods and Result: We measured the Sigmar1 expression level in CryAB R120G hearts and found that endogenous Sigmar1 protein and transcript levels are substantially reduced in CryAB R120G hearts. To test the functional role of Sigmar1 in a proteotoxic model of heart failure in vivo , we crossed the Sigmar1 knockout mouse with the CryAB R120G mouse to generate Sigmar1 ablated CryAB R120G mouse (CryAB R120G xSigmar1 -/- ). Echocardiographic analysis showed the age-dependent aggravation of cardiac dysfunction in the CryAB R120G xSigmar1 -/- mice compared to CryAB R120G mice. Masson’s Trichrome staining also showed increased cardiac fibrosis in the CryAB R120G xSigmar1 -/- mice hearts. Sigmar1 ablation in CryAB R120G mice hearts resulted in increased protein aggregate content measurement by immunostaining and aggregate size measured by electron microscopy. Sigmar1 siRNA-knockdown in CryAB R120G expressing cardiomyocytes also led to a dramatic increase in aggregate size and content. Conclusion: Overall, we found that Sigmar1 plays a vital role in the degradation of protein aggregates in the heart. Sigmar1 knockdown in CryAB R120G hearts promoted interstitial fibrosis, aggravated ventricular dysfunction, cardiac hypertrophy, and increased protein aggregates.