Cardiac Hypertrophy - Ca(2+)-dependent NF-AT signaling in Cardiac Hypertrophy

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(Ca2+)-dependent NFAT signaling in cardiac hypertrophy

Cardiac hypertrophy defined as a compensatory mechanism of the heart that helps to maintain cardiac output during pathological states. Hypertrophy leads to pathologic cardiac growth, and is associated with increased morbidity and mortality. Transcription factor NF-AT3 (NFATc4) plays a critical role in Ca(2+)/calcineurin-mediated cardiac hypertrophic signaling. NF-AT3 signaling is essential for normal cardiac valve and may be adapted specifically for transducing pathologic signals into a hypertrophic response in the heart [1], [2].

GPCRs (G-protein coupled receptors) play an important role in the regulation of cardiac function and adaptation to changes in hemodynamic burden. GPCRs involved in cardiac hypertrophy are mainly represented by Angiotensin II receptor type-1, Alpha-1A and Alpha-1B adrenergic receptors and Beta-1 adrenergic receptor. Angiotensin II is a multifunctional hormone which influences functions of cardiovascular cells initiated by its interaction with Angiotensin II receptor, type-1 [3], [4]. Alpha-1 adrenergic receptors and Beta-1 adrenergic receptor activated by Phenylephrine and Noradrenaline appear to be specifically required for a cardiac hypertrophic response [5], [6].

These GPCRs are coupled to three principal classes of heterotrimeric GTP-binding proteins, G-alphaS, G-alphaI and G-alphaQ/11 which transduce signals towards intracellular effectors such as enzymes and ion channels. G-proteins consist of the subunits G-alpha (G-protein alpha-s, G-protein alpha-i family, G-protein alpha-q/11 or G-protein alpha-q and G-protein alpha-11) and G-beta/gamma (G-proteins beta/gamma), which dissociate upon receptor activation and independently activate intracellular signaling pathways [4], [7], [8], [9].

Activation of phospholipase C (PLC-beta1 and PLC-beta3) leads to the hydrolysis of membrane phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), resulted in inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) production [4], [10]. IP3 binds to IP3 receptor on the surface of the endoplasmic reticulum leading to release of Ca(2+) ions. DAG and Ca(2+) activate diverse isoforms of Protein kinase C (PKC), including PKC-alpha, PKC-beta and PKC-gamma [11], [12], [13]. Increase of DAG intracellular level leads to the opening of DAG-sensitive ion channels (such as TRPC3 and TRPC6), independently of PKC signaling [14], [15].

Activation of PKC also regulates changes in Ca(2+) intracellular levels via phosphorylation of channels and pumps (such as TRPC6, NCX1 and L-type Ca(II) channel) that leads to the opening of channels and Ca(2+) influx [16], [17], [18], [19], [20], followed by activation of Na+/H+ exchanger (SLC9A1). Ca(2+)-dependent regulatory factor, Calmodulin, physically interacts with SLC9A1, thus resulting in activation of Na+/H+ exchange by increases in intracellular Ca(2+) level [21].

G-protein alpha-s activated by Beta-1 adrenergic receptor in cardiac tissues stimulates two Adenylate cyclases, Adenylate cyclase type V and Adenylate cyclase type VI, and subsequent cAMP (cyclic Adenosine-3',5' Monophosphate) formation [22], [23], [24]. Subsequently, activation of cAMP-dependent Protein kinase A (PKA) that consists of regulatory (PKA-reg (cAMP-dependent)) and catalytic subunits (PKA-cat (cAMP-dependent)) leads to phosphorylation of a set of regulatory proteins, including activation of L-type Ca(II) channel. The PKA and PKC signaling pathways co-operate to increase this channel's activity by pre-association of the channel with PKC isoforms and phosphorylation of L-type Ca(II) channel, alpha 1C subunit, by PKA. It is a key mechanism of intracellular Ca(2+) increase in the cardiac response to hormonal regulation [18].

Calcineurin A is a calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the nucleus through dephosphorylation and translocation of nuclear transcription factors NFATs [25]. NF-AT3 (NF-ATc4) plays a critical role in calcineurin-mediated cardiac hypertrophic signaling [26].

In the nucleus, NF-AT3 cooperates with other transcription factors such as GATA-4, NKX-2.5, MEF2 (MEF2A, MEF2C, MEF2D), HAND1 and HAND2, leading to activation of transcription of genes, essential for cardiac development, and, thus, hypertrophy [27], [28], [29].

References:

  1. Olson EN, Molkentin JD
    Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circulation research 1999 Apr 2;84(6):623-32
  2. Molkentin JD
    Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovascular research 2004 Aug 15;63(3):467-75
  3. Touyz RM, Berry C
    Recent advances in angiotensin II signaling. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 2002 Sep;35(9):1001-15
  4. Bai H, Wu LL, Xing DQ, Liu J, Zhao YL
    Angiotensin II induced upregulation of G alpha q/11, phospholipase C beta 3 and extracellular signal-regulated kinase 1/2 via angiotensin II type 1 receptor. Chinese medical journal 2004 Jan;117(1):88-93
  5. Iwata M, Maturana A, Hoshijima M, Tatematsu K, Okajima T, Vandenheede JR, Van Lint J, Tanizawa K, Kuroda S
    PKCepsilon-PKD1 signaling complex at Z-discs plays a pivotal role in the cardiac hypertrophy induced by G-protein coupling receptor agonists. Biochemical and biophysical research communications 2005 Feb 25;327(4):1105-13
  6. Liggett SB
    Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify. The Journal of clinical investigation 2006 Apr;116(4):875-7
  7. Zhang L, Li L, Wu LL
    [Alterations of G proteins in heart diseases]. Sheng li ke xue jin zhan [Progress in physiology] 2003 Jan;34(1):32-6
  8. Levy BI
    How to explain the differences between renin angiotensin system modulators. American journal of hypertension 2005 Sep;18(9 Pt 2):134S-141S
  9. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  10. Dent MR, Dhalla NS, Tappia PS
    Phospholipase C gene expression, protein content, and activities in cardiac hypertrophy and heart failure due to volume overload. American journal of physiology. Heart and circulatory physiology 2004 Aug;287(2):H719-27
  11. Jalili T, Takeishi Y, Song G, Ball NA, Howles G, Walsh RA
    PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. The American journal of physiology 1999 Dec;277(6 Pt 2):H2298-304
  12. Dorn GW 2nd, Force T
    Protein kinase cascades in the regulation of cardiac hypertrophy. The Journal of clinical investigation 2005 Mar;115(3):527-37
  13. Sentex E, Wang X, Liu X, Lukas A, Dhalla NS
    Expression of protein kinase C isoforms in cardiac hypertrophy and heart failure due to volume overload. Canadian journal of physiology and pharmacology 2006 Feb;84(2):227-38
  14. Venkatachalam K, Zheng F, Gill DL
    Regulation of canonical transient receptor potential (TRPC) channel function by diacylglycerol and protein kinase C. The Journal of biological chemistry 2003 Aug 1;278(31):29031-40
  15. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H
    TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. The EMBO journal 2006 Nov 15;25(22):5305-16
  16. Iwamoto T, Pan Y, Wakabayashi S, Imagawa T, Yamanaka HI, Shigekawa M
    Phosphorylation-dependent regulation of cardiac Na+/Ca2+ exchanger via protein kinase C. The Journal of biological chemistry 1996 Jun 7;271(23):13609-15
  17. Schulze DH, Muqhal M, Lederer WJ, Ruknudin AM
    Sodium/calcium exchanger (NCX1) macromolecular complex. The Journal of biological chemistry 2003 Aug 1;278(31):28849-55
  18. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
  19. Kim JY, Saffen D
    Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. The Journal of biological chemistry 2005 Sep 9;280(36):32035-47
  20. Saleh SN, Albert AP, Peppiatt CM, Large WA
    Angiotensin II activates two cation conductances with distinct TRPC1 and TRPC6 channel properties in rabbit mesenteric artery myocytes. The Journal of physiology 2006 Dec 1;577(Pt 2):479-95
  21. Counillon L, Pouysségur J
    The expanding family of eucaryotic Na(+)/H(+) exchangers. The Journal of biological chemistry 2000 Jan 7;275(1):1-4
  22. Wolf MJ, Tachibana H, Rockman HA
    Methods for the detection of altered beta-adrenergic receptor signaling pathways in hypertrophied hearts. Methods in molecular medicine 2005;112:353-62
  23. Ishikawa Y, Iwatsubo K, Tsunematsu T, Okumura S
    Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy. Biochemical Society transactions 2005 Dec;33(Pt 6):1337-40
  24. Timofeyev V, He Y, Tuteja D, Zhang Q, Roth DM, Hammond HK, Chiamvimonvat N
    Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy. Journal of molecular and cellular cardiology 2006 Jul;41(1):170-81
  25. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD
    Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circulation research 2004 Jan 9;94(1):110-8
  26. Sugden PH
    Signaling in myocardial hypertrophy: life after calcineurin? Circulation research 1999 Apr 2;84(6):633-46
  27. Morkin E
    Control of cardiac myosin heavy chain gene expression. Microscopy research and technique 2000 Sep 15;50(6):522-31
  28. Pu WT, Ma Q, Izumo S
    NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circulation research 2003 Apr 18;92(7):725-31
  29. Akazawa H, Komuro I
    Roles of cardiac transcription factors in cardiac hypertrophy. Circulation research 2003 May 30;92(10):1079-88

  1. Olson EN, Molkentin JD
    Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? Circulation research 1999 Apr 2;84(6):623-32
  2. Molkentin JD
    Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovascular research 2004 Aug 15;63(3):467-75
  3. Touyz RM, Berry C
    Recent advances in angiotensin II signaling. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 2002 Sep;35(9):1001-15
  4. Bai H, Wu LL, Xing DQ, Liu J, Zhao YL
    Angiotensin II induced upregulation of G alpha q/11, phospholipase C beta 3 and extracellular signal-regulated kinase 1/2 via angiotensin II type 1 receptor. Chinese medical journal 2004 Jan;117(1):88-93
  5. Iwata M, Maturana A, Hoshijima M, Tatematsu K, Okajima T, Vandenheede JR, Van Lint J, Tanizawa K, Kuroda S
    PKCepsilon-PKD1 signaling complex at Z-discs plays a pivotal role in the cardiac hypertrophy induced by G-protein coupling receptor agonists. Biochemical and biophysical research communications 2005 Feb 25;327(4):1105-13
  6. Liggett SB
    Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify. The Journal of clinical investigation 2006 Apr;116(4):875-7
  7. Zhang L, Li L, Wu LL
    [Alterations of G proteins in heart diseases]. Sheng li ke xue jin zhan [Progress in physiology] 2003 Jan;34(1):32-6
  8. Levy BI
    How to explain the differences between renin angiotensin system modulators. American journal of hypertension 2005 Sep;18(9 Pt 2):134S-141S
  9. Wettschureck N, Offermanns S
    Mammalian G proteins and their cell type specific functions. Physiological reviews 2005 Oct;85(4):1159-204
  10. Dent MR, Dhalla NS, Tappia PS
    Phospholipase C gene expression, protein content, and activities in cardiac hypertrophy and heart failure due to volume overload. American journal of physiology. Heart and circulatory physiology 2004 Aug;287(2):H719-27
  11. Jalili T, Takeishi Y, Song G, Ball NA, Howles G, Walsh RA
    PKC translocation without changes in Galphaq and PLC-beta protein abundance in cardiac hypertrophy and failure. The American journal of physiology 1999 Dec;277(6 Pt 2):H2298-304
  12. Dorn GW 2nd, Force T
    Protein kinase cascades in the regulation of cardiac hypertrophy. The Journal of clinical investigation 2005 Mar;115(3):527-37
  13. Sentex E, Wang X, Liu X, Lukas A, Dhalla NS
    Expression of protein kinase C isoforms in cardiac hypertrophy and heart failure due to volume overload. Canadian journal of physiology and pharmacology 2006 Feb;84(2):227-38
  14. Venkatachalam K, Zheng F, Gill DL
    Regulation of canonical transient receptor potential (TRPC) channel function by diacylglycerol and protein kinase C. The Journal of biological chemistry 2003 Aug 1;278(31):29031-40
  15. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H
    TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. The EMBO journal 2006 Nov 15;25(22):5305-16
  16. Iwamoto T, Pan Y, Wakabayashi S, Imagawa T, Yamanaka HI, Shigekawa M
    Phosphorylation-dependent regulation of cardiac Na+/Ca2+ exchanger via protein kinase C. The Journal of biological chemistry 1996 Jun 7;271(23):13609-15
  17. Schulze DH, Muqhal M, Lederer WJ, Ruknudin AM
    Sodium/calcium exchanger (NCX1) macromolecular complex. The Journal of biological chemistry 2003 Aug 1;278(31):28849-55
  18. Yang L, Liu G, Zakharov SI, Morrow JP, Rybin VO, Steinberg SF, Marx SO
    Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms. The Journal of biological chemistry 2005 Jan 7;280(1):207-14
  19. Kim JY, Saffen D
    Activation of M1 muscarinic acetylcholine receptors stimulates the formation of a multiprotein complex centered on TRPC6 channels. The Journal of biological chemistry 2005 Sep 9;280(36):32035-47
  20. Saleh SN, Albert AP, Peppiatt CM, Large WA
    Angiotensin II activates two cation conductances with distinct TRPC1 and TRPC6 channel properties in rabbit mesenteric artery myocytes. The Journal of physiology 2006 Dec 1;577(Pt 2):479-95
  21. Counillon L, Pouysségur J
    The expanding family of eucaryotic Na(+)/H(+) exchangers. The Journal of biological chemistry 2000 Jan 7;275(1):1-4
  22. Wolf MJ, Tachibana H, Rockman HA
    Methods for the detection of altered beta-adrenergic receptor signaling pathways in hypertrophied hearts. Methods in molecular medicine 2005;112:353-62
  23. Ishikawa Y, Iwatsubo K, Tsunematsu T, Okumura S
    Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy. Biochemical Society transactions 2005 Dec;33(Pt 6):1337-40
  24. Timofeyev V, He Y, Tuteja D, Zhang Q, Roth DM, Hammond HK, Chiamvimonvat N
    Cardiac-directed expression of adenylyl cyclase reverses electrical remodeling in cardiomyopathy. Journal of molecular and cellular cardiology 2006 Jul;41(1):170-81
  25. Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD
    Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circulation research 2004 Jan 9;94(1):110-8
  26. Sugden PH
    Signaling in myocardial hypertrophy: life after calcineurin? Circulation research 1999 Apr 2;84(6):633-46
  27. Morkin E
    Control of cardiac myosin heavy chain gene expression. Microscopy research and technique 2000 Sep 15;50(6):522-31
  28. Pu WT, Ma Q, Izumo S
    NFAT transcription factors are critical survival factors that inhibit cardiomyocyte apoptosis during phenylephrine stimulation in vitro. Circulation research 2003 Apr 18;92(7):725-31
  29. Akazawa H, Komuro I
    Roles of cardiac transcription factors in cardiac hypertrophy. Circulation research 2003 May 30;92(10):1079-88

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