Mast Cells Contribute to Pressure Overload-Induced Myocardial Hypertrophy by Upregulating TRPV4 via Histamine: Role of Ca2+/ CnA/NFATc3 Signaling Pathway

Abstract

Objective

To investigate whether cardiac mast cells (MCs) participate in pressure overload-induced myocardial hypertrophy through the regulation of transient receptor potential vanilloid 4 (TRPV4).

Methods

Pressure overload-induced myocardial hypertrophy was induced via abdominal aortic constriction (AAC). Myocardial hypertrophy was evaluated by measuring the heart weight index (HW/BW), lung weight index (LW/BW), ratio of heart weight to tibia length (HW/TL), ratio of lung weight to tibia length (LW/TL), and cross-sectional area of myocardial cells. qRT-PCR was used to detect the mRNA expression of TRPV4. Western blotting was used to detect the protein expression of TRPV4, mast cell tryptase, myosin heavy chain beta (β-MHC), calcineurin A (CnA), and nuclear factor of activated T-cell c3 (NFATc3). ELISA was used to measure the levels of brain natriuretic peptide (BNP) and histamine. Fluo4 AM was used to detect the calcium signal in H9c2 myocardial cells.

Results

Compared with those of the sham rats, the myocardial mast cells, tryptase, HW/BW, LW/BW, HW/TL, and LW/TL, the cross-sectional area of the myocardial cells, and the expression of β-MHC, TRPV4, CnA, and NFATc3 in the myocardial tissue and the serum BNP of the AAC-treated rats increased significantly, whereas the MC stabilizer cromolyn sodium (CS) reversed these indicators. In H9c2 cardiomyocytes, treatment with histamine and the TRPV4 agonist GSK1016790A upregulated the expression of TRPV4, β-MHC, BNP, CnA and NFATc3 and increased calcium ion influx, whereas these effects were inhibited by the H2 receptor inhibitor famotidine and the TRPV4 inhibitor HC067047.

Conclusion

Cardiac MCs participate in pressure overload-induced myocardial hypertrophy through the upregulation of TRPV4 via its mediator histamine, and the Ca²⁺/CnA/NFATc3 signaling pathway is involved in this process.

References

[1] Lyon RC, Zanella F, Omens JH, et al.. Mechanotransduction in cardiac hypertrophy and failure. Circ Res, 2015, 116(8): 1462-1476

[2] Hou J, Kang YJ. Regression of pathological cardiac hypertrophy: Signaling pathways and therapeutic targets. Pharmacol Ther, 2012, 135(3): 337-354

[3] Strassheim D, Dempsey EC, Gerasimovskaya E, et al.. Role of inflammatory cell subtypes in heart failure. J Immunol Res, 2019, 2019: 2164017

[4] Sawada H, Saito T, Nickel NP, et al.. Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med, 2014, 211(2): 263-280

[5] Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol, 2014, 11(5): 255-265

[6] Gröschel C, Sasse A, Monecke S, et al.. CD8⁺-T cells with specificity for a model antigen in cardiomyocytes can become activated after transverse aortic constriction but do not accelerate progression to heart failure. Front Immunol, 2018, 9: 2665

[7] Nevers T, Salvador AM, Grodecki-Pena A, et al.. Left ventricular t-cell recruitment contributes to the pathogenesis of heart failure. Circ Hear Fail, 2015, 8(4): 776-787

[8] Levick SP, Melndez GC, Plante E, et al.. Cardiac mast cells: The centrepiece in adverse myocardial remodelling. Cardiovasc Res, 2011, 89(1): 12-19

[9] Ong SF, Rose NR, Čiháková D. Natural killer cells in inflammatory heart disease. Clin Immunol, 2017, 175: 26-33

[10] Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci, 2014, 71(4): 549-574

[11] Gees M, Colsoul B, Nilius B. The role of transient receptor potential cation channels in Ca²⁺ signaling. Cold Spring Harb Perspect Biol, 2010, 2(10): a003962

[12] Mulier M, Vriens J, Voets T. TRP channel pores and local calcium signals. Cell Calcium, 2017, 66: 19-24

[13] Li H. TRP Channel Classification. Adv Exp Med Biol, 2017, 976: 1-8

[14] Kuwahara K, Hill JA, Olson EN, et al.. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest, 2006, 116(12): 3114-3126

[15] Nakayama H, Wilkin BJ, Bodi I, et al.. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J, 2006, 20(10): 1660-1670

[16] Eder P, Molkentin JD. TRPC channels as effectors of cardiac hypertrophy. Circ Res, 2011, 108(2): 265-272

[17] Zhang Q, Qi H, Cao Y, et al.. Activation of transient receptor potential vanilloid 3 channel (TRPV3) aggravated pathological cardiac hypertrophy via calcineurin/NFATc3 pathway in rats. J Cell Mol Med, 2018, 22(12): 6055-6067

[18] Wang Z, Xu Y, Wang M, et al.. TRPA1 inhibition ameliorates pressure overload-induced cardiac hypertrophy and fibrosis in mice. EBioMedicine, 2018, 36: 54-62

[19] Wu QF, Qian C, Zhao N, et al.. Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes. Cell Death Dis, 2017, 8(5): e28282017

[20] Bers DM, Guo TAO. Calcium Signaling in Cardiac Ventricular Myocytes. Ann N Y Acad Sci, 2005, 1047: 86-98

[21] Ding W, Dong M, Deng J, et al.. Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca²⁺ handling and calcineurin-NFAT signaling pathway. Am J Physiol Hear Circ Physiol, 2014, 307(5): H792-H802

[22] Bush EW, Hood DB, Papst PJ, et al.. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling. J Biol Chem, 2006, 281(44): 33487-33496

[23] Palaniyandi SS, Inagaki K, Mochly-Rosen D. Mast cells and epsilonPKC: A role in cardiac remodeling in hypertension-induced heart failure. J Mol Cell Cardiol, 2008, 45(6): 779-786

[24] Legere SA, Haidl ID, Légaré JF, et al.. Mast cells in cardiac fibrosis: New insights suggest opportunities for intervention. Front Immunol, 2019, 10: 580

[25] Wang H, Da Silva J, Alencar A, et al.. Mast Cell Inhibition Attenuates Cardiac Remodeling and Diastolic Dysfunction in Middle-aged, Ovariectomized Fischer 344 × Brown Norway Rats. J Cardiovasc Pharmacol, 2016, 68(1): 49-57

[26] Liu X, Shi GP, Guo J. Innate Immune Cells in Pressure Overload-Induced Cardiac Hypertrophy and Remodeling. Front Cell Dev Biol, 2021, 9: 659666

[27] Levick SP, McLarty JL, Murray DB, et al.. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension, 2009, 53(6): 1041-1047

[28] Janicki JS, Brower GL, Gardner JD, et al.. Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overload. Cardiovasc Res, 2006, 69(3): 657-665

[29] Theoharides TC, Kempuraj D, Tagen M, et al.. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev, 2007, 217: 65-78

[30] Xiong X, Li J, Zhang S, et al.. Involvement of Polyamines From Cardiac Mast Cells in Myocardial Remodeling Induced by Pressure Overload Through Mitochondrial Permeability Transition Pore Opening. Front Cardiovasc Med, 2022, 9: 850688

[31] Chen M, Xin J, Liu B, et al.. Mitogen-Activated Protein Kinase and Intracellular Polyamine Signaling Is Involved in TRPV1 Activation-Induced Cardiac Hypertrophy. J Am Heart Assoc, 2016, 5(8): e003718

[32] Koch SE, Mann A, Jones S, et al.. Transient receptor potential vanilloid 2 function regulates cardiac hypertrophy via stretch-induced activation. J Hypertens, 2017, 35(3): 602-611

[33] Thoppil RJ, Adapala RK, Cappelli HC, et al.. TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation. Sci Rep, 2015, 5: 14257

[34] Gorbunov AS, Maslov LN, Jaggi AS, et al.. Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart. Curr Cardiol Rev, 2019, 15(4): 244-251

[35] Zou Y, Zhang M, Wu Q, et al.. Activation of transient receptor potential vanilloid 4 is involved in pressure overload-induced cardiac hypertrophy. Elife, 2022, 11: e74519

[36] Kreusser MM, Lehmann LH, Keranov S, et al.. Cardiac CaM kinase II genes δ and γ contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. Circulation, 2014, 130(15): 1262-127

[37] Chung E, Yeung F, Leinwand LA. Calcineurin activity is required for cardiac remodelling in pregnancy. Cardiovasc Res, 2013, 100(3): 402-410

[38] Lunde IG, Aronsen JM, Melleby AO, et al.. Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy. Mol Biol Rep, 2022, 49(12): 11795-11809

[39] Kirschmer N, Bandleon S, Von Ehrlich-Treuenstä Tt V, et al.. TRPC4α and TRPC4β similarly affect neonatal cardiomyocyte survival during chronic GPCR stimulation. PLoS One, 2016, 11(12): e0168446

[40] Kecskés M, Jacobs G, Kerselaers S, et al.. The Ca²⁺-activated cation channel TRPM4 is a negative regulator of angiotensin II-induced cardiac hypertrophy. Basic Res Cardiol, 2015, 110(4): 43