Top

Published in:

01-11-2015 | Original Contribution

Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction

Authors: Liangpeng Li, Xiaodi Wang, Wen Chen, Haoyu Qi, Ding-Sheng Jiang, Ling Huang, Fuhua Huang, Liming Wang, Hongliang Li, Xin Chen

Published in: Basic Research in Cardiology | Issue 6/2015

Abstract

Caspase activation and recruitment domain 3 (CARD3) is a caspase recruitment domain (CARD)-containing serine/threonine kinase and plays a pivotal role in apoptosis, immunity, tissue development and proliferation. To date, the causal relationship between CARD3 and myocardial infarction (MI) remains largely unexplored. This study aimed to identify the functional significance of CARD3 in the regulation of cardiac remodelling after MI and the underlying mechanisms of its effects. The levels of CARD3 expression were up-regulated in failing human and mouse post-infarction hearts. In addition, CARD3-knockout (KO) mice and transgenic mice overexpressing CARD3 in the heart were then generated and subjected to MI. Compared with wild-type (WT) control mice, CARD3-KO mice developed smaller infarct sizes, improved survival rates, and preserved left ventricle (LV) function after MI. Significantly, CARD3-KO hearts had less cardiomyocyte apoptosis and inflammatory cell infiltration in the infarct border zone. Attenuated LV remodelling was also observed in the KO hearts following MI, with reduced cardiac hypertrophy and fibrosis. Conversely, CARD3 overexpression resulted in the opposite MI-induced phenotype. Similar results were observed in ex vivo-cultured neonatal rat cardiomyocytes exposed to hypoxia. Mechanistically, we discovered that the CARD3-mediated detrimental effects of MI were associated with the activation of the NF-κB and p38 signalling cascades. Taken together, these data demonstrate that CARD3 serves as a novel positive modulator of ventricular remodelling after MI via the regulation of the NF-κB and p38 signalling. Thus, CARD3 may be a promising therapeutic target for the treatment of heart failure after MI.

Available only for authorised users

Abe J, Baines CP, Berk BC (2000) Role of mitogen-activated protein kinases in ischemia and reperfusion injury: the good and the bad. Circ Res 86:607–609CrossRefPubMed

Chandrashekhar Y, Sen S, Anway R, Shuros A, Anand I (2004) Long-term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction. J Am Coll Cardiol 43:295–301CrossRefPubMed

Chen K, Gao L, Liu Y, Zhang Y, Jiang DS, Wei X, Zhu XH, Zhang R, Chen Y, Yang Q, Kioka N, Zhang XD, Li H (2013) Vinexin-beta protects against cardiac hypertrophy by blocking the Akt-dependent signalling pathway. Basic Res Cardiol 108:338. doi:10.1007/s00395-013-0338-0 CrossRefPubMed

Dorn GW 2nd (2009) Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81:465–473. doi:10.1093/cvr/cvn243 PubMedCentralCrossRefPubMed

Du X, Jiang S, Liu H, Xin X, Li J, Geng M, Jiang H (2010) MS80, a novel sulfated polysaccharide, inhibits CD40-NF-kappaB pathway via targeting RIP2. Mol Cell Biochem 337:277–285. doi:10.1007/s11010-009-0309-9 CrossRefPubMed

Engelbrecht AM, Niesler C, Page C, Lochner A (2004) p38 and JNK have distinct regulatory functions on the development of apoptosis during simulated ischaemia and reperfusion in neonatal cardiomyocytes. Basic Res Cardiol 99:338–350. doi:10.1007/s00395-004-0478-3 CrossRefPubMed

Feuerstein GZ, Young PR (2000) Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways. Cardiovasc Res 45:560–569CrossRefPubMed

Frangogiannis NG (2014) The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities. J Cardiovasc Pharmacol 63:185–195. doi:10.1097/FJC.0000000000000003 PubMedCentralCrossRefPubMed

Gajarsa JJ, Kloner RA (2011) Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities. Heart Fail Rev 16:13–21. doi:10.1007/s10741-010-9181-7 CrossRefPubMed

10.

Gallagher G, Menzie S, Huang Y, Jackson C, Hunyor SN (2007) Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheep. Basic Res Cardiol 102:63–72. doi:10.1007/s00395-006-0610-7 CrossRefPubMed

11.

Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2014) Heart disease and stroke statistics–2014 update: a report from the American Heart Association. Circulation 129:e28–e292. doi:10.1161/01.cir.0000441139.02102.80 CrossRef

12.

Gottlieb RA (2003) Mitochondrial signaling in apoptosis: mitochondrial daggers to the breaking heart. Basic Res Cardiol 98:242–249. doi:10.1007/s00395-003-0404-0 PubMed

13.

Heusch G (2013) Cardioprotection: chances and challenges of its translation to the clinic. Lancet 381:166–175. doi:10.1016/S0140-6736(12)60916-7 CrossRefPubMed

14.

Heusch G, Kleinbongard P, Skyschally A (2013) Myocardial infarction and coronary microvascular obstruction: an intimate, but complicated relationship. Basic Res Cardiol 108:380. doi:10.1007/s00395-013-0380-y CrossRefPubMed

15.

Heusch G, Libby P, Gersh B, Yellon D, Bohm M, Lopaschuk G, Opie L (2014) Cardiovascular remodelling in coronary artery disease and heart failure. Lancet 383:1933–1943. doi:10.1016/S0140-6736(14)60107-0 PubMedCentralCrossRefPubMed

16.

Heusch P, Canton M, Aker S, van de Sand A, Konietzka I, Rassaf T, Menazza S, Brodde OE, Di Lisa F, Heusch G, Schulz R (2010) The contribution of reactive oxygen species and p38 mitogen-activated protein kinase to myofilament oxidation and progression of heart failure in rabbits. Br J Pharmacol 160:1408–1416. doi:10.1111/j.1476-5381.2010.00793.x PubMedCentralCrossRefPubMed

17.

Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M (2004) Inhibition of p38 MAP kinase- and RICK/NF-kappaB-signaling suppresses inflammatory bowel disease. FASEB J 18:1550–1552. doi:10.1096/fj.04-1642fje PubMed

18.

Inohara N, Koseki T, Lin J, del Peso L, Lucas PC, Chen FF, Ogura Y, Nunez G (2000) An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem 275:27823–27831. doi:10.1074/jbc.M003415200 PubMed

19.

Jacquet S, Nishino Y, Kumphune S, Sicard P, Clark JE, Kobayashi KS, Flavell RA, Eickhoff J, Cotten M, Marber MS (2008) The role of RIP2 in p38 MAPK activation in the stressed heart. J Biol Chem 283:11964–11971. doi:10.1074/jbc.M707750200 PubMedCentralCrossRefPubMed

20.

Jiang DS, Li L, Huang L, Gong J, Xia H, Liu X, Wan N, Wei X, Zhu X, Chen Y, Chen X, Zhang XD, Li H (2014) Interferon regulatory factor 1 is required for cardiac remodeling in response to pressure overload. Hypertension 64:77–86. doi:10.1161/HYPERTENSIONAHA.114.03229 CrossRefPubMed

21.

Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G, Janeway CA, Medzhitov R, Flavell RA (2002) RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–199. doi:10.1038/416194a CrossRefPubMed

22.

Landmesser U, Wollert KC, Drexler H (2009) Potential novel pharmacological therapies for myocardial remodelling. Cardiovasc Res 81:519–527. doi:10.1093/cvr/cvn317 CrossRefPubMed

23.

Levin MC, Jirholt P, Wramstedt A, Johansson ME, Lundberg AM, Trajkovska MG, Stahlman M, Fogelstrand P, Brisslert M, Fogelstrand L, Yan ZQ, Hansson GK, Bjorkbacka H, Olofsson SO, Boren J (2011) Rip2 deficiency leads to increased atherosclerosis despite decreased inflammation. Circ Res 109:1210–1218. doi:10.1161/CIRCRESAHA.111.246702 CrossRefPubMed

24.

Li HL, Zhuo ML, Wang D, Wang AB, Cai H, Sun LH, Yang Q, Huang Y, Wei YS, Liu PP, Liu DP, Liang CC (2007) Targeted cardiac overexpression of A20 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circulation 115:1885–1894. doi:10.1161/CIRCULATIONAHA.106.656835 CrossRefPubMed

25.

Li L, Chen W, Zhu Y, Wang X, Jiang DS, Huang F, Wang L, Xiang F, Qin W, Wang Q, Zhang R, Zhu X, Li H, Chen X (2014) Caspase recruitment domain 6 protects against cardiac hypertrophy in response to pressure overload. Hypertension 64:94–102. doi:10.1161/HYPERTENSIONAHA.113.03021 CrossRefPubMed

26.

Li S, Zhong S, Zeng K, Luo Y, Zhang F, Sun X, Chen L (2010) Blockade of NF-kappaB by pyrrolidine dithiocarbamate attenuates myocardial inflammatory response and ventricular dysfunction following coronary microembolization induced by homologous microthrombi in rats. Basic Res Cardiol 105:139–150. doi:10.1007/s00395-009-0067-6 CrossRefPubMed

27.

Lu J, Bian ZY, Zhang R, Zhang Y, Liu C, Yan L, Zhang SM, Jiang DS, Wei X, Zhu XH, Chen M, Wang AB, Chen Y, Yang Q, Liu PP, Li H (2013) Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol 108:326. doi:10.1007/s00395-012-0326-9 CrossRefPubMed

28.

Marber MS, Rose B, Wang Y (2011) The p38 mitogen-activated protein kinase pathway–a potential target for intervention in infarction, hypertrophy, and heart failure. J Mol Cell Cardiol 51:485–490. doi:10.1016/j.yjmcc.2010.10.021 PubMedCentralCrossRefPubMed

29.

Martindale JJ, Wall JA, Martinez-Longoria DM, Aryal P, Rockman HA, Guo Y, Bolli R, Glembotski CC (2005) Overexpression of mitogen-activated protein kinase kinase 6 in the heart improves functional recovery from ischemia in vitro and protects against myocardial infarction in vivo. J Biol Chem 280:669–676. doi:10.1074/jbc.M406690200 PubMedCentralCrossRefPubMed

30.

Maulik N, Sato M, Price BD, Das DK (1998) An essential role of NFkappaB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. FEBS Lett 429:365–369CrossRefPubMed

31.

McCain ML, Sheehy SP, Grosberg A, Goss JA, Parker KK (2013) Recapitulating maladaptive, multiscale remodeling of failing myocardium on a chip. Proc Natl Acad Sci USA 110:9770–9775. doi:10.1073/pnas.1304913110 PubMedCentralCrossRefPubMed

32.

McCarthy JV, Ni J, Dixit VM (1998) RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem 273:16968–16975CrossRefPubMed

33.

Munz B, Hildt E, Springer ML, Blau HM (2002) RIP2, a checkpoint in myogenic differentiation. Mol Cell Biol 22:5879–5886PubMedCentralCrossRefPubMed

34.

Muslin AJ (2008) MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets. Clin Sci Lond 115:203–218. doi:10.1042/CS20070430 PubMedCentralCrossRefPubMed

35.

Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94:1543–1553. doi:10.1161/01.RES.0000130526.20854.fa CrossRefPubMed

36.

Onai Y, Suzuki J, Maejima Y, Haraguchi G, Muto S, Itai A, Isobe M (2007) Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction. Am J Physiol Heart Circ Physiol 292:H530–H538. doi:10.1152/ajpheart.00549.2006 CrossRefPubMed

37.

Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA (2006) Controversies in ventricular remodelling. Lancet 367:356–367. doi:10.1016/S0140-6736(06)68074-4 CrossRefPubMed

38.

Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M, Body-Malapel M, Inohara N, Nunez G (2007) RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178:2380–2386CrossRefPubMed

39.

Penna C, Perrelli MG, Pagliaro P (2013) Mitochondrial pathways, permeability transition pore, and redox signaling in cardioprotection: therapeutic implications. Antioxid Redox Signal 18:556–599. doi:10.1089/ars.2011.4459 CrossRefPubMed

40.

Prech M, Marszalek A, Schroder J, Filas V, Lesiak M, Jemielity M, Araszkiewicz A, Grajek S (2010) Apoptosis as a mechanism for the elimination of cardiomyocytes after acute myocardial infarction. Am J Cardiol 105:1240–1245. doi:10.1016/j.amjcard.2009.12.039 CrossRefPubMed

41.

Rahman MA, Sundaram K, Mitra S, Gavrilin MA, Wewers MD (2014) Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death. PLoS One 9:e92731. doi:10.1371/journal.pone.0092731 PubMedCentralCrossRefPubMed

42.

Ren J, Zhang S, Kovacs A, Wang Y, Muslin AJ (2005) Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J Mol Cell Cardiol 38:617–623. doi:10.1016/j.yjmcc.2005.01.012 CrossRefPubMed

43.

Schulz R, Aker S, Belosjorow S, Konietzka I, Rauen U, Heusch G (2003) Stress kinase phosphorylation is increased in pacing-induced heart failure in rabbits. Am J Physiol Heart Circ Physiol 285:H2084–H2090. doi:10.1152/ajpheart.01038.2002 CrossRefPubMed

44.

See F, Thomas W, Way K, Tzanidis A, Kompa A, Lewis D, Itescu S, Krum H (2004) p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. J Am Coll Cardiol 44:1679–1689. doi:10.1016/j.jacc.2004.07.038 CrossRefPubMed

45.

Sicard P, Jacquet S, Kobayashi KS, Flavell RA, Marber MS (2009) Pharmacological postconditioning effect of muramyl dipeptide is mediated through RIP2 and TAK1. Cardiovasc Res 83:277–284. doi:10.1093/cvr/cvp055 PubMedCentralCrossRefPubMed

46.

Sutton MG, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2988CrossRefPubMed

47.

Tang TT, Yuan J, Zhu ZF, Zhang WC, Xiao H, Xia N, Yan XX, Nie SF, Liu J, Zhou SF, Li JJ, Yao R, Liao MY, Tu X, Liao YH, Cheng X (2012) Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol 107:232. doi:10.1007/s00395-011-0232-6 CrossRefPubMed

48.

Timmers L, van Keulen JK, Hoefer IE, Meijs MF, van Middelaar B, den Ouden K, van Echteld CJ, Pasterkamp G, de Kleijn DP (2009) Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ Res 104:699–706. doi:10.1161/CIRCRESAHA.108.189746 CrossRefPubMed

49.

Usluoglu N, Pavlovic J, Moelling K, Radziwill G (2007) RIP2 mediates LPS-induced p38 and IkappaBalpha signaling including IL-12 p40 expression in human monocyte-derived dendritic cells. Eur J Immunol 37:2317–2325. doi:10.1002/eji.200636388 CrossRefPubMed

50.

Valen G (2004) Signal transduction through nuclear factor kappa B in ischemia-reperfusion and heart failure. Basic Res Cardiol 99:1–7. doi:10.1007/s00395-003-0442-7 CrossRefPubMed

51.

van den Borne SW, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J (2010) Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7:30–37. doi:10.1038/nrcardio.2009.199 CrossRefPubMed

52.

Wang Y (2007) Mitogen-activated protein kinases in heart development and diseases. Circulation 116:1413–1423. doi:10.1161/CIRCULATIONAHA.106.679589 CrossRefPubMed

53.

Xiao J, Moon M, Yan L, Nian M, Zhang Y, Liu C, Lu J, Guan H, Chen M, Jiang D, Jiang H, Liu PP, Li H (2012) Cellular FLICE-inhibitory protein protects against cardiac remodelling after myocardial infarction. Basic Res Cardiol 107:239. doi:10.1007/s00395-011-0239-z CrossRefPubMed

54.

Yang F, Liu YH, Yang XP, Xu J, Kapke A, Carretero OA (2002) Myocardial infarction and cardiac remodelling in mice. Exp Physiol 87:547–555CrossRefPubMed

55.

Yin X, Krikorian P, Logan T, Csizmadia V (2010) Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism. Mol Cell Biochem 333:251–259. doi:10.1007/s11010-009-0226-y CrossRefPubMed

56.

Yoshida K, Yoshiyama M, Omura T, Nakamura Y, Kim S, Takeuchi K, Iwao H, Yoshikawa J (2001) Activation of mitogen-activated protein kinases in the non-ischemic myocardium of an acute myocardial infarction in rats. Jpn Circ J 65:808–814CrossRefPubMed

57.

Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59. doi:10.1038/nrm2308 CrossRefPubMed

58.

Zhang WH, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci USA 100:16012–16017. doi:10.1073/pnas.2534856100 PubMedCentralCrossRefPubMed

59.

Zhang Y, Liu X, She ZG, Jiang DS, Wan N, Xia H, Zhu XH, Wei X, Zhang XD, Li H (2014) Interferon regulatory factor 9 is an essential mediator of heart dysfunction and cell death following myocardial ischemia/reperfusion injury. Basic Res Cardiol 109:434. doi:10.1007/s00395-014-0434-9 CrossRefPubMed

Title: Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction
Authors: Liangpeng Li
Xiaodi Wang
Wen Chen
Haoyu Qi
Ding-Sheng Jiang
Ling Huang
Fuhua Huang
Liming Wang
Hongliang Li
Xin Chen
Publication date: 01-11-2015
Publisher: Springer Berlin Heidelberg
Published in: Basic Research in Cardiology / Issue 6/2015
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-015-0515-4

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Regulatory role of CARD3 in left ventricular remodelling and dysfunction after myocardial infarction

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2015

Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction

TRPV4 channels: physiological and pathological role in cardiovascular system

Elevated mean neutrophil volume represents altered neutrophil composition and reflects damage after myocardial infarction

Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy

Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia

Cardioprotective effects of early and late aerobic exercise training in experimental pulmonary arterial hypertension

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page