Identification of Fat Storage-Inducing Transmembrane Proteins 1 and 2 as Putative Therapeutic Targets for Heart Failure by Integrated Analysis of Proteome and Transcriptome

Abstract

Cardiovascular disease constitutes a major health burden globally, for which novel cardiotonic agents are still required. Cardiac failure is thought to be caused by dysfunctions of the sarcoplasmic/endoplasmic reticulum (SR/ ER) in cardiomyocytes. Therefore, in this study, we searched for novel pharmaceutical targets in SR/ER. Tissue and organelle specific proteome profiling by liquid chromatography coupled with mass spectrometry after gel electrophoresis separation identified 3,638 proteins in heart and liver SR/ER samples from a mouse transverse aortic constriction (TAC) model (heart failure). We also analyzed the transcriptome of heart tissue from the TAC model (heart failure, hypertrophy) and a myocardial infarction model using microarrays to identify differentially expressed genes in the diseased heart. Several genes were chosen for further studies following the proteome and transcriptome analyses. Of these, fat storage-inducing transmembrane proteins 1 and 2 (FITM1 and FITM2) were highly expressed in mouse and human heart and skeletal muscle. We investigated the functions of FITM1 and FITM2 in vitro and confirmed that they mediated lipid droplet (LD) formation and directly bound to triglycerides. FITM1 and/ or FITM2 overexpression in cells altered the levels of Ero1-Lα and PDI, which are ER stress marker proteins that protect against heart failure and affect cellular metabolism. Together, these results indicate that FITM1 and FITM2 are expressed in heart tissue and that their modulated expression or function can change LD formation, ER function, and cellular metabolism in cells. Thus, FITM1 and FITM2 are good drug target candidates. Tmem38A: Transmembrane Protein 38A; Tmem38B: Transmembrane Protein 38B; Tmem242: Transmembrane Protein 242; UPR: Unfolded Protein Response.