Mapping the proteomic and human genomic bridge of the cardiac Striatin interactome identifies unique molecular signature between diabetes and heart remodeling

Abstract Background Diabetic cardiomyopathy (DbCM) is a major cardiac complication characterized by a maladaptive remodeling and metabolic dysfunction of the heart of diabetic patients. Striatin (STRN) is a multifaceted protein that regulates cardiomyocyte contraction and binds metabolic regulators implicated in diabetes, yet the identification of its interactors along with their function in the diabetic heart are elusive. Purpose In this study, we aimed to construct the STRN protein network in the remodeled diabetic heart and explore its functional signature. We also opted to map the single nucleotide polymorphisms (SNPs) in the human orthologues of these proteins to bridge the genetic information to the signaling molecules that translate metabolic stress to maladaptive functional changes. Methods We used proteins from left ventricles (LVs) of diabetic rats and immunoprecipitation (IP) with a STRN-specific antibody, combined to proteomics and genomics (bioinformatics). Results Diabetic rats exhibited pronounced cardiac remodeling, marked by an increased heart weight-to-body weight ratio, heightened Atrial Natriuretic Factor (ANF) expression, and altered alpha-to-beta myosin heavy chain isoform balance. Interestingly, STRN expression followed a similar pattern to ANF across all cardiac chambers, suggesting a potential role for STRN in the maladaptive remodeling of these hearts. Analysis of the STRN protein complex in normal and diabetic LVs identified 103 proteins at the intersection of glucose metabolism, diabetes, cardiac remodeling, and DbCM, out of which 10 genes (PPARG, ADIPOQ, TNF, IL6, LEP, INSR, IRS1, GLUT4, GCK, and HNF1A) carry SNPs specifically linked to DbCM. These imprinted genetic variants are associated with metabolic dysregulation, insulin signaling, and inflammation, all of which contribute to the progression of DbCM. While interrogating the STRN interactome only in the diabetic LVs, pathways governing ERK1/2 signaling, mitochondrial gene regulation, hexose metabolism, and platelet activation surfaced thus reinforcing their role in diabetic myocardial dysfunction. Conversely, cardiac remodeling-related SNPs out of this group of STRN interactors highlighted motor proteins, actomyosin structure organization, tight junctions, and cell polarity maintenance, underscoring cytoskeletal and contractile alterations in DbCM. ACTB and MYH14 emerged as key genetic intersection points, carrying SNPs linked to both diabetes and cardiac remodeling, highlighting a previously unrecognized proteomic/genetic bridge between metabolic dysregulation and structural adaptation in DbCM. Conclusion The presence of DbCM-associated human SNPs within the STRN protein complex crystallizes its role as a genetic and molecular link between metabolic stress and cardiac remodeling, potentially influencing the disease susceptibility and progression. These results provide novel therapeutic targets for DbCM and offer hope for better guided therapy for diabetes.