BMP‑2 alleviates heart failure with type 2 diabetes mellitus and doxorubicin‑induced AC16 cell injury by inhibiting NLRP3 inflammasome‑mediated pyroptosis

Zhang,Jia-Mei; Yu,Rui-Qun; Wu,Feng-Zhu; Qiao,Liang; Wu,Xiao-Rong; Fu,Ying-Jie; Liang,Yue-Feng; Pang,Yu; Xie,Chun-Yi

doi:10.3892/etm.2021.10329

BMP‑2 alleviates heart failure with type 2 diabetes mellitus and doxorubicin‑induced AC16 cell injury by inhibiting NLRP3 inflammasome‑mediated pyroptosis

Authors:
- Jia-Mei Zhang
- Rui-Qun Yu
- Feng-Zhu Wu
- Liang Qiao
- Xiao-Rong Wu
- Ying-Jie Fu
- Yue-Feng Liang
- Yu Pang
- Chun-Yi Xie
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Affiliations: Department of Cardiovascular Medicine, Shanghai TCM‑Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, P.R. China
Published online on: June 23, 2021 https://doi.org/10.3892/etm.2021.10329
Article Number: 897

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Abstract

Chronic heart failure (CHF) and diabetes mellitus are associated with morbidity and mortality. CHF and diabetes generally simultaneously occur, resulting in adverse outcomes. Diabetes complicates cardiomyopathy and exacerbates heart failure conditions. An increase in natriuretic peptides, including atrial natriuretic peptide (ANP), and another endsogenously generated peptide, brain natriuretic peptide (BNP), serves an essential role in CHF. The aim of this study was to explore the molecular regulation between bone morphogenetic protein‑2 (BMP‑2) and ANP or BNP in diabetes‑associated cardiomyopathy. In total, 25 serum samples were collected from patients with CHF with or without type 2 diabetes mellitus to compare with 25 controls. Cardiomyopathy and hyperglycemia were induced in rats by doxorubicin and streptozotocin, respectively. AC16 cells were used to study molecular mechanisms. BMP, ANP and BNP concentration in patients and rats were measured by ELISA. Flow cytometry was performed to analyze cell pyroptosis and ROS production. Reverse transcription‑quantitative PCR and western blotting were used to examine mRNA and protein expression of NOD‑, LRR‑ and pyrin domain‑containing protein 3 (NLRP3), pro‑caspase‑1, caspase‑1 (p20) and gasdermin D. BMP‑2 was negatively correlated with ANP and BNP in CHF patients with type 2 diabetes mellitus. Similar results were obtained in rats and AC16 cells. BMP‑2 decreased the NLRP3 inflammasome activation and cell pyroptosis. The present study found evidence that the cardioprotective effects of BMP‑2 act through ANP and BNP both in vivo and in vitro. BMP‑2 inhibits inflammasome formation. The results suggested that BMP‑2 may serve as a novel therapeutic target for the treatment of diabetic heart conditions.

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1	Khan H, Anker SD, Januzzi JL Jr, McGuire DK, Sattar N, Woerle HJ and Butler J: Heart failure epidemiology in patients with diabetes mellitus without coronary heart disease. J Card Fail. 25:78–86. 2019.PubMed/NCBI View Article : Google Scholar
2	Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation. 112:e154–e235. 2005.PubMed/NCBI View Article : Google Scholar
3	Dunlay SM, Givertz MM, Aguilar D, Allen LA, Chan M, Desai AS, Deswal A, Dickson VV, Kosiborod MN, Lekavich CL, et al: Type 2 diabetes mellitus and heart failure, a scientific statement from the American heart association and heart failure society of America. J Card Fail. 25:584–619. 2019.PubMed/NCBI View Article : Google Scholar
4	Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL and Goff DC Jr: Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 27:699–703. 2004.PubMed/NCBI View Article : Google Scholar
5	Cullan A, Grover M and Hitchcock K: FPIN's clinical inquiries: Brain natriuretic peptide for ruling out heart failure. Am Fam Physician. 83:1333–1334. 2011.PubMed/NCBI
6	Kalra PR, Anker SD and Coats AJ: Water and sodium regulation in chronic heart failure: The role of natriuretic peptides and vasopressin. Cardiovasc Res. 51:495–509. 2001.PubMed/NCBI View Article : Google Scholar
7	Broz P: Immunology: Caspase target drives pyroptosis. Nature. 526:642–643. 2015.PubMed/NCBI View Article : Google Scholar
8	Danelishvili L and Bermudez LE: Analysis of pyroptosis in bacterial infection. Methods Mol Biol. 1004:67–73. 2013.PubMed/NCBI View Article : Google Scholar
9	Liu X, Zhang Z, Ruan J, Pan Y, Magupalli VG, Wu H and Lieberman J: Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 535:153–158. 2016.PubMed/NCBI View Article : Google Scholar
10	Tavakolizadeh J, Roshanaei K, Salmaninejad A, Yari R, Nahand JS, Sarkarizi HK, Mousavi SM, Salarinia R, Rahmati M, Mousavi SF, et al: MicroRNAs and exosomes in depression: Potential diagnostic biomarkers. J Cell Biochem. 119:3783–3797. 2018.PubMed/NCBI View Article : Google Scholar
11	Qiu Z, Lei S, Zhao B, Wu Y, Su W, Liu M, Meng Q, Zhou B, Leng Y and Xia ZY: NLRP3 inflammasome activation-mediated pyroptosis aggravates myocardial ischemia/reperfusion injury in diabetic rats. Oxid Med Cell Longev. 2017(9743280)2017.PubMed/NCBI View Article : Google Scholar
12	Wang J, Greene SB and Martin JF: BMP signaling in congenital heart disease: New developments and future directions. Birth Defects Res A Clin Mol Teratol. 91:441–448. 2011.PubMed/NCBI View Article : Google Scholar
13	Miyazono K, Kamiya Y and Morikawa M: Bone morphogenetic protein receptors and signal transduction. J Biochem. 147:35–51. 2010.PubMed/NCBI View Article : Google Scholar
14	Zheng M, Zhu J, Lv T, Liu L, Sun H and Tian J: Bone morphogenetic protein-2 enhances the expression of cardiac transcription factors by increasing histone H3 acetylation in H9c2 cells. Mol Med Rep. 7:953–958. 2013.PubMed/NCBI View Article : Google Scholar
15	Lu J, Sun B, Huo R, Wang YC, Yang D, Xing Y, Xiao XL, Xie X and Dong DL: Bone morphogenetic protein-2 antagonizes bone morphogenetic protein-4 induced cardiomyocyte hypertrophy and apoptosis. J Cell Physiol. 229:1503–1510. 2014.PubMed/NCBI View Article : Google Scholar
16	Tokola H, Rysä J, Pikkarainen S, Hautala N, Leskinen H, Kerkelä R, Ilves M, Aro J, Vuolteenaho O, Ritvos O and Ruskoaho H: Bone morphogenetic protein-2-a potential autocrine/paracrine factor in mediating the stretch activated B-type and atrial natriuretic peptide expression in cardiac myocytes. Mol Cell Endocrinol. 399:9–21. 2015.PubMed/NCBI View Article : Google Scholar
17	Izumi M, Masaki M, Hiramoto Y, Sugiyama S, Kuroda T, Terai K, Hori M, Kawase I and Hirota H: Cross-talk between bone morphogenetic protein 2 and leukemia inhibitory factor through ERK 1/2 and Smad1 in protection against doxorubicin-induced injury of cardiomyocytes. J Mol Cell Cardiol. 40:224–233. 2006.PubMed/NCBI View Article : Google Scholar
18	Panahi G, Pasalar P, Zare M, Rizzuto R and Meshkani R: High glucose induces inflammatory responses in HepG2 cells via the oxidative stress-mediated activation of NF-κB, and MAPK pathways in HepG2 cells. Arch Physiol Biochem. 124:468–474. 2018.PubMed/NCBI View Article : Google Scholar
19	Wree A, Eguchi A, McGeough MD, Pena CA, Johnson CD, Canbay A, Hoffman HM and Feldstein AE: NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 59:898–910. 2014.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Ahmad S, Panda BP, Kohli K, Fahim M and Dubey K: Folic acid ameliorates celecoxib cardiotoxicity in a doxorubicin heart failure rat model. Pharm Biol. 55:1295–1303. 2017.PubMed/NCBI View Article : Google Scholar
22	Malka A, Ertracht O, Bachner-Hinenzon N, Reiter I and Binah O: The cardioprotective efficacy of TVP1022 against ischemia/reperfusion injury and cardiac remodeling in rats. Pharmacol Res Perspect. 4(e00272)2016.PubMed/NCBI View Article : Google Scholar
23	Ma H, Kong J, Wang YL, Li JL, Hei NH, Cao XR, Yang JJ, Yan WJ, Liang WJ, Dai HY and Dong B: Angiotensin-converting enzyme 2 overexpression protects against doxorubicin-induced cardiomyopathy by multiple mechanisms in rats. Oncotarget. 8:24548–24563. 2017.PubMed/NCBI View Article : Google Scholar
24	Arias T, Chen J, Fayad ZA, Fuster V, Hajjar RJ and Chemaly ER: Comparison of echocardiographic measurements of left ventricular volumes to full volume magnetic resonance imaging in normal and diseased rats. J Am Soc Echocardiogr. 26:910–918. 2013.PubMed/NCBI View Article : Google Scholar
25	Xu X, Philip JL, Razzaque MA, Lloyd JW, Muller CM and Akhter SA: High-molecular-weight polyethylene glycol inhibits myocardial ischemia-reperfusion injury in vivo. J Thorac Cardiovasc Surg. 149:588–593. 2015.PubMed/NCBI View Article : Google Scholar
26	Diez J: Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: Implications for therapy. Eur J Heart Fail. 19:167–176. 2017.PubMed/NCBI View Article : Google Scholar
27	Meng L, Lin H, Zhang J, Lin N, Sun Z, Gao F, Luo H, Ni T, Luo W, Chi J and Guo H: Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J Mol Cell Cardiol. 136:15–26. 2019.PubMed/NCBI View Article : Google Scholar
28	Cai CL, Zhou W, Yang L, Bu L, Qyang Y, Zhang X, Li X, Rosenfeld MG, Chen J and Evans S: T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis. Development. 132:2475–2487. 2005.PubMed/NCBI View Article : Google Scholar
29	Chen D, Zhao M and Mundy GR: Bone morphogenetic proteins. Growth Factors. 22:233–241. 2004.PubMed/NCBI View Article : Google Scholar
30	Rivera-Feliciano J and Tabin CJ: Bmp2 instructs cardiac progenitors to form the heart-valve-inducing field. Dev Biol. 295:580–588. 2006.PubMed/NCBI View Article : Google Scholar
31	Sánchez-de-Diego C, Valer JA, Pimenta-Lopes C, Rosa JL and Ventura F: Interplay between BMPs and reactive oxygen species in cell signaling and pathology. Biomolecules. 9(534)2019.PubMed/NCBI View Article : Google Scholar
32	Li S, Wang G, Gao LR, Lu WH, Wang XY, Chuai M, Lee KK, Cao L and Yang X: Autophagy is involved in ethanol-induced cardia bifida during chick cardiogenesis. Cell Cycle. 14:3306–3317. 2015.PubMed/NCBI View Article : Google Scholar
33	Hruska KA, Mathew S and Saab G: Bone morphogenetic proteins in vascular calcification. Circ Res. 97:105–114. 2005.PubMed/NCBI View Article : Google Scholar
34	Li X, Du N, Zhang Q, Li J, Chen X, Liu X, Hu Y, Qin W, Shen N, Xu C, et al: MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy. Cell Death Dis. 5(e1479)2014.PubMed/NCBI View Article : Google Scholar
35	Sanders LN, Schoenhard JA, Saleh MA, Mukherjee A, Ryzhov S, McMaster WG Jr, Nolan K, Gumina RJ, Thompson TB, Magnuson MA, et al: BMP antagonist gremlin 2 limits inflammation after myocardial infarction. Circ Res. 119:434–449. 2016.PubMed/NCBI View Article : Google Scholar
36	Jafarinezhad Z, Rafati A, Ketabchi F, Noorafshan A and Karbalay-Doust S: Cardioprotective effects of curcumin and carvacrol in doxorubicin-treated rats: Stereological study. Food Sci Nutr. 7:3581–3588. 2019.PubMed/NCBI View Article : Google Scholar
37	Reagan WJ, York M, Berridge B, Schultze E, Walker D and Pettit S: Comparison of cardiac troponin I and T, including the evaluation of an ultrasensitive assay, as indicators of doxorubicin-induced cardiotoxicity. Toxicol Pathol. 41:1146–1158. 2013.PubMed/NCBI View Article : Google Scholar
38	El-Sayed el SM, Mansour AM and Abdul-Hameed MS: Thymol and carvacrol prevent doxorubicin-induced cardiotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol. 30:37–44. 2016.PubMed/NCBI View Article : Google Scholar
39	Ji GG, Shu JT, Zhang M, Ju XJ, Shan YJ, Liu YF and Tu YJ: Transcriptional regulatory region and DNA methylation analysis of TNNI1 gene promoters in Gaoyou duck skeletal muscle (Anas platyrhynchos domestica). Br Poult Sci. 60:202–208. 2019.PubMed/NCBI View Article : Google Scholar
40	Milano S, Carmosino M, Gerbino A, Svelto M and Procino G: Hereditary nephrogenic diabetes insipidus: Pathophysiology and possible treatment. An update. Int J Mol Sci. 18(2385)2017.PubMed/NCBI View Article : Google Scholar
41	Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schütz G, Lumeng CN and Mortensen RM: Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J Clin Invest. 120:3350–3364. 2010.PubMed/NCBI View Article : Google Scholar
42	Yao J, Liu Z, Ma W, Dong W, Wang Y, Zhang H, Zhang M and Sun D: Three-dimensional coating of SF/PLGA coaxial nanofiber membranes on surfaces of calcium phosphate cement for enhanced bone regeneration. ACS Biomater Sci Eng. 6:2970–2984. 2020.PubMed/NCBI View Article : Google Scholar
43	Chen J and Chen ZJ: PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 564:71–76. 2018.PubMed/NCBI View Article : Google Scholar