HDAC1 Promotes Myocardial Fibrosis in Diabetic Cardiomyopathy by Inhibiting BMP-7 Transcription Through Histone Deacetylation

Abstract

Objective Diabetic cardiomyopathy (DCM) constitutes a primary cause of mortality in diabetic patients. Histone deacetylase (HDAC) inhibition can alleviate diabetes-associated myocardial injury. This study investigated the mechanism of HDAC1 on myocardial fibrosis (MF) in DCM.

Methods A murine model of DCM was established by a high-fat diet and streptozotocin injection. The bodyweight, blood glucose, serum insulin, and cardiac function of mice were analyzed. Lentivirus-packaged sh-HDAC1 was injected into DCM mice and high glucose (HG)-induced cardiac fibroblasts (CFs). The pathological structure of the myocardium and the level of myocardial fibrosis were observed by histological staining. HDAC1 expression in mouse myocardial tissues and CFs was determined. Collagen I, collagen III, alpha-smooth muscle actin (α-SMA), and vimentin levels in CFs were detected, and CF proliferation was tested. HDAC activity and histone acetylation levels in tissues and cells were measured. Bone morphogenetic protein-7 (BMP-7) expression in myocardial tissues and CFs was determined. Functional rescue experiments were conducted to confirm the effects of histone acetylation and BMP-7 on myocardial fibrosis.

Results DCM mice showed decreased bodyweight, elevated blood glucose and serum insulin, and cardiac dysfunction. Elevated HDAC1 and reduced BMP-7 expressions were detected in DCM mice and HG-induced CFs. HDAC1 repressed BMP-7 transcription through deacetylation. HDAC1 silencing alleviated MF, reduced CF proliferation and decreased collagen I, -III, α-SMA, and vimentin levels. However, reducing histone acetylation level or BMP-7 downregulation reversed the effects of HDAC1 silencing on CF fibrosis.

Conclusion HDAC1 repressed BMP-7 transcription by enhancing histone deacetylation, thereby promoting MF and aggravating DCM.

Key words

HDAC1 - diabetic cardiomyopathy - myocardial fibrosis - histone acetylation - BMP-7 - cardiac fibroblasts

• References

• 1 Blair M. Diabetes mellitus review. Urol Nurs 2016; 36: 27-36
• 2 Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 2020; 16: 377-390
• 3 Wang AJ, Wang S, Wang BJ. et al. Epigenetic regulation associated with sirtuin 1 in complications of diabetes mellitus. Front Endocrinol (Lausanne) 2020; 11: 598012
• 4 Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: A hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia 2018; 61: 21-28
• 5 Dillmann WH. Diabetic cardiomyopathy. Circ Res 2019; 124: 1160-1162
• 6 Stratton MS, McKinsey TA. Epigenetic regulation of cardiac fibrosis. J Mol Cell Cardiol 2016; 92: 206-213
• 7 Singh GB, Sharma R, Khullar M. Epigenetics and diabetic cardiomyopathy. Diabetes Res Clin Pract 2011; 94: 14-21
• 8 Ganesan A. Epigenetics: The first 25 centuries. Philos Trans R Soc Lond B Biol Sci 2018; 373: 20170067
• 9 Xu Z, Tong Q, Zhang Z. et al. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin Sci (Lond) 2017; 131: 1841-1857
• 10 Bagchi RA, Weeks KL. Histone deacetylases in cardiovascular and metabolic diseases. J Mol Cell Cardiol 2019; 130: 151-159
• 11 Chen Y, Du J, Zhao YT. et al. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol 2015; 14: 99
• 12 Lee TI, Kao YH, Tsai WC. et al. HDAC inhibition modulates cardiac PPARs and fatty acid metabolism in diabetic cardiomyopathy. PPAR Res 2016; 2016: 5938740
• 13 Du W, Wang N, Li F. et al. STAT3 phosphorylation mediates high glucose-impaired cell autophagy in an HDAC1-dependent and -independent manner in Schwann cells of diabetic peripheral neuropathy. FASEB J 2019; 33: 8008-8021
• 14 Guo CJ, Xie JJ, Hong RH. et al. Puerarin alleviates streptozotocin (STZ)-induced osteoporosis in rats through suppressing inflammation and apoptosis via HDAC1/HDAC3 signaling. Biomed Pharmacother 2019; 115: 108570
• 15 Williams SM, Golden-Mason L, Ferguson BS. et al. Class I HDACs regulate angiotensin II-dependent cardiac fibrosis via fibroblasts and circulating fibrocytes. J Mol Cell Cardiol 2014; 67: 112-125
• 16 Nural-Guvener HF, Zakharova L, Nimlos J. et al. HDAC class I inhibitor, Mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+cardiac myofibroblast activation. Fibrogenesis Tissue Repair 2014; 7: 10
• 17 Yu XY, Geng YJ, Liang JL. et al. High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor. Exp Cell Res 2010; 316: 2903-2909
• 18 Aluganti Narasimhulu C, Singla DK. The role of bone morphogenetic protein 7 (BMP-7) in inflammation in heart diseases. Cells 2020; 9: 280
• 19 Jin Y, Cheng X, Lu J. et al. Exogenous BMP-7 facilitates the recovery of cardiac function after acute myocardial infarction through counteracting TGF-beta1 signaling pathway. Tohoku J Exp Med 2018; 244: 1-6
• 20 Urbina P, Singla DK. BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2014; 307: H762-H772
• 21 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402-408
• 22 Deng M, Yang S, Ji Y. et al. Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts. J Cell Mol Med 2020; 24: 5249-5259
• 23 Medzikovic L, Heese H, van Loenen PB. et al. Nuclear receptor nur77 controls cardiac fibrosis through distinct actions on fibroblasts and cardiomyocytes. Int J Mol Sci 2021; 22: 1600
• 24 Kong L, Wang H, Li C. et al. Sulforaphane ameliorates diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7. Diabetes Metab J 2021; 45: 909-920
• 25 Meng Q, Zhai X, Yuan Y. et al. LncRNA ZEB1-AS1 inhibits high glucose-induced EMT and fibrogenesis by regulating the miR-216a-5p/BMP7 axis in diabetic nephropathy. Braz J Med Biol Res 2020; 53: e9288
• 26 Lorenzo-Almoros A, Tunon J, Orejas M. et al. Diagnostic approaches for diabetic cardiomyopathy. Cardiovasc Diabetol 2017; 16: 28
• 27 Bush EW, McKinsey TA. Protein acetylation in the cardiorenal axis: The promise of histone deacetylase inhibitors. Circ Res 2010; 106: 272-284
• 28 Shinde AV, Humeres C, Frangogiannis NG. The role of alpha-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 298-309
• 29 Tarbit E, Singh I, Peart JN. et al. Biomarkers for the identification of cardiac fibroblast and myofibroblast cells. Heart Fail Rev 2019; 24: 1-15
• 30 Nagao K, Inada T, Tamura A. et al. Circulating markers of collagen types I, III, and IV in patients with dilated cardiomyopathy: Relationships with myocardial collagen expression. ESC Heart Fail 2018; 5: 1044-1051
• 31 Lin C, Wei D, Xin D. et al. Ellagic acid inhibits proliferation and migration of cardiac fibroblasts by down-regulating expression of HDAC1. J Toxicol Sci 2019; 44: 425-433
• 32 Rai R, Sun T, Ramirez V. et al. Acetyltransferase p300 inhibitor reverses hypertension-induced cardiac fibrosis. J Cell Mol Med 2019; 23: 3026-3031
• 33 Chen X, Xu J, Jiang B. et al. Bone morphogenetic protein-7 antagonizes myocardial fibrosis induced by atrial fibrillation by restraining transforming growth factor-beta (TGF-beta)/Smads signaling. Med Sci Monit 2016; 22: 3457-3468