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… Show more
“…It would be interesting to analyze the effects of their deletion in chronic heart failure induced by MI, and the mechanistic insights together with that in TAC model. Previously, we found that Fitm1 were identified by proteomic analysis of endoplasmic reticulum/sarcoplasmic rich fraction of mice heart, but there was no significant difference between TAC-operated and sham mice, probably because, the protein expression changed little as a result of TAC [9]. Therefore, it also would be important to analyze the detailed protein expression pattern in both heart failure model.Fig.…”
Section: Resultsmentioning
confidence: 94%
“…Recently, we found that these proteins were identified in mice and/or human heart samples by proteomic analysis, affected the cardiovascular system and body development in zebrafish, and that their modulated expression or function can change lipid droplet formation, ER function, and cellular metabolism in cells [9] . These data suggested their potential to modulate heart failure pathogenesis.…”
Fat storage-inducing transmembrane proteins 1 and 2 (FITM1 and FITM2, respectively) are transmembrane endoplasmic/sarcoplasmic reticulum proteins involved in lipid droplet formation. The physiological functions of FITM1 have only been reported in skeletal muscle, while those of FITM2 were analyzed using genetically engineered mice. However, their roles in the heart have not been characterized. To examine their cardiac functions, we analyzed Fitm1- or Fitm2-knockout mice. Neither constitutive Fitm1 (−/−) aged nor heart failure model mice showed significant differences in heart size or function. Fitm2 (−/−) mice exhibited embryonic death, and aged Fitm2 (+/−) mice had shortened left ventricular end-diastolic dimension, and shortened left ventricular end-systolic dimension. However, body weight and ejection fraction of Fitm2 (+/−) mice were similar to those of wild-type littermates. In the chronic heart failure models, Fitm2 (+/−) mice showed significant suppression of increased left ventricular end-diastolic dimension and reduced ejection fraction. These results suggest the involvement of Fitm2 in chronic heart failure, whereas Fitm1 have a minor effect in this context in mice.
“…It would be interesting to analyze the effects of their deletion in chronic heart failure induced by MI, and the mechanistic insights together with that in TAC model. Previously, we found that Fitm1 were identified by proteomic analysis of endoplasmic reticulum/sarcoplasmic rich fraction of mice heart, but there was no significant difference between TAC-operated and sham mice, probably because, the protein expression changed little as a result of TAC [9]. Therefore, it also would be important to analyze the detailed protein expression pattern in both heart failure model.Fig.…”
Section: Resultsmentioning
confidence: 94%
“…Recently, we found that these proteins were identified in mice and/or human heart samples by proteomic analysis, affected the cardiovascular system and body development in zebrafish, and that their modulated expression or function can change lipid droplet formation, ER function, and cellular metabolism in cells [9] . These data suggested their potential to modulate heart failure pathogenesis.…”
Fat storage-inducing transmembrane proteins 1 and 2 (FITM1 and FITM2, respectively) are transmembrane endoplasmic/sarcoplasmic reticulum proteins involved in lipid droplet formation. The physiological functions of FITM1 have only been reported in skeletal muscle, while those of FITM2 were analyzed using genetically engineered mice. However, their roles in the heart have not been characterized. To examine their cardiac functions, we analyzed Fitm1- or Fitm2-knockout mice. Neither constitutive Fitm1 (−/−) aged nor heart failure model mice showed significant differences in heart size or function. Fitm2 (−/−) mice exhibited embryonic death, and aged Fitm2 (+/−) mice had shortened left ventricular end-diastolic dimension, and shortened left ventricular end-systolic dimension. However, body weight and ejection fraction of Fitm2 (+/−) mice were similar to those of wild-type littermates. In the chronic heart failure models, Fitm2 (+/−) mice showed significant suppression of increased left ventricular end-diastolic dimension and reduced ejection fraction. These results suggest the involvement of Fitm2 in chronic heart failure, whereas Fitm1 have a minor effect in this context in mice.
“…Compromised mitochondrial activity is a common feature in hearts under ischemic stresses, and an increase in mitochondrial biogenesis is considered a promising therapeutic strategy to treat ischemic heart disease 7 . FAM210A was previously reported to be reduced by 34% in murine hearts at the mRNA level under MI versus sham surgical conditions by a microarray-based transcriptome screening 32 . After examining the expression of FAM210A in human HF samples, we found that FAM210A protein expression was significantly decreased in the hearts of ischemic HF (IHF) patients compared to non-failing human hearts (Figure 7A).…”
Aims: Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodeling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo. Methods and Results: Tamoxifen-induced MHCMCM-driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response (ISR), resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodeling and damage in ischemia-induced heart failure. Conclusion: These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischemic heart disease.
“…The immunoprecipitated samples were separated by SDS-PAGE and gel portions corresponding to 150-200 kDa were excised. The in-gel digest was conducted as described [9]. For the multiple reaction monitoring (MRM) assay, the internal standard (IS) peptide mixture was spiked to the digested peptides.…”
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