HIMF overexpression induced cardiomyocyte hypertrophy, while HIMF knockdown and gene ablation attenuated hypertrophic remodeling and cardiac dysfunction via calcium-dependent and HIF-1α pathways.
Does HIMF modulation affect the development of cardiac hypertrophy in preclinical models?
HIMF plays a critical role in the development of cardiac hypertrophy via calcium-dependent and HIF-1α mechanisms, identifying it as a potential therapeutic target for heart disease.
HIMF (hypoxia-induced mitogenic factor/found in inflammatory zone 1/resistin like α) is a secretory and cytokine-like protein and serves as a critical stimulator of hypoxia-induced pulmonary hypertension. With a role for HIMF in heart disease unknown, we explored the possible roles for HIMF in cardiac hypertrophy by overexpressing and knocking down HIMF in cardiomyocytes and characterizing HIMF gene ( himf ) knockout mice. We found that HIMF mRNA and protein levels were upregulated in phenylephrine-stimulated cardiomyocyte hypertrophy and our mouse model of transverse aortic constriction–induced cardiac hypertrophy, as well as in human hearts with dilated cardiomyopathy. Furthermore, HIMF overexpression could induce cardiomyocyte hypertrophy, as characterized by elevated protein expression of hypertrophic biomarkers (ANP atrial natriuretic peptide and β-MHC myosin heavy chain-β) and increased cell-surface area compared with controls. Conversely, HIMF knockdown prevented phenylephrine-induced cardiomyocyte hypertrophy and himf ablation in knockout mice significantly attenuated transverse aortic constriction–induced hypertrophic remodeling and cardiac dysfunction. HIMF overexpression increased the cytosolic Ca 2+ concentration and activated the CaN–NFAT (calcineurin–nuclear factor of activated T cell) and MAPK (mitogen-activated protein kinase) pathways; this effect could be prevented by reducing cytosolic Ca 2+ concentration with L-type Ca 2+ channel blocker nifedipine or inhibiting the CaSR (Ca 2+ sensing receptor) with Calhex 231. Furthermore, HIMF overexpression increased HIF-1α (hypoxia-inducible factor) expression in neonatal rat ventricular myocytes, and HIMF knockout inhibited HIF-1α upregulation in transverse aortic constriction mice. Knockdown of HIF-1α attenuated HIMF-induced cardiomyocyte hypertrophy. In conclusion, HIMF has a critical role in the development of cardiac hypertrophy, and targeting HIMF may represent a potential therapeutic strategy.
Kumar et al. (2018) studied Cardiac hypertrophy. HIMF overexpression and knockdown vs. Controls was evaluated on Cardiomyocyte hypertrophy and cardiac dysfunction. HIMF overexpression induced cardiomyocyte hypertrophy, while HIMF knockdown and gene ablation attenuated hypertrophic remodeling and cardiac dysfunction via calcium-dependent and HIF-1α pathways.