Mib2 Regulates Lipid Metabolism in Heart Failure With Preserved Ejection Fraction via the Runx2–Hmgcs2 Axis

ABSTRACT Obesity and the mismanagement of lipids significantly contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, the underlying molecular mechanisms that regulate the metabolic changes and disruptions in lipid balance within HFpEF remain to be fully understood. Transcriptome data for HFpEF were sourced from the National Center for Biotechnology Information (NCBI) database. A mouse model for HFpEF was developed utilising leptin‐deficient (ob/ob) mice. The cardiac‐specific mind bomb E3 ubiquitin protein ligase 2 (Mib2) overexpression in ob/ob mice was achieved by tail vein injection of a recombinant adeno‐associated virus serotype 9 vector carrying Mib2 with a cTNT promoter (AAV9‐cTNT‐Mib2). In vitro, neonatal rat ventricular myocytes were exposed to fatty acid to induce lipotoxicity. The molecular mechanisms were investigated through proteomic analysis, dual luciferase reporter gene assay, and immunoprecipitation assays. GO and KEGG enrichment analyses indicated that the differentially expressed proteins (DEPs) in HFpEF were prominently enriched in pathways related to the fatty acid metabolic process. The transcriptomic and proteomic analyses of heart tissues from HFpEF mice presented a notable elevation in the expression of 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (Hmgcs2). Immunoprecipitation assays revealed that mind bomb 2 (Mib2) directly interacted with runt‐related transcription factor 2 (Runx2), ubiquitinating and degrading Runx2 to inhibit Hmgcs2 transcription, impeding the fatty acid metabolic process. Mice with cardiac‐specific overexpression of Mib2 displayed a more pronounced progression of cardiac dysfunction and an accumulation of lipids compared to the control group. Our research uncovers a mechanism by which Mib2 modulates cardiac lipid metabolic homeostasis in HFpEF, implicating the Runx2‐Hmgcs2 axis.