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Basic Research in Cardiology
Published in: Basic Research in Cardiology 5/2010

Open Access 01-09-2010 | Original Contribution

Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2

Authors: Michael Klaiber, Martin Kruse, Katharina Völker, Juliane Schröter, Robert Feil, Marc Freichel, Andrea Gerling, Susanne Feil, Alexander Dietrich, Juan Eduardo Camacho Londoño, Hideo A. Baba, Joel Abramowitz, Lutz Birnbaumer, Josef M. Penninger, Olaf Pongs, Michaela Kuhn

Published in: Basic Research in Cardiology | Issue 5/2010

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Abstract

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on β-adrenergic versus Angiotensin II (Ang II)-dependent (Gs vs. Gαq mediated) modulation of Ca2+ i-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca2+ currents and Ca2+ i transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca2+ currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca2+/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, β-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca2+-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca2+ i-dependent hypertrophic growth response to Ang II, but not to β-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT1 signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for β-adrenergic Ca2+ i-stimulation in adult myocytes.
Literature
1.
Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49 ReviewCrossRefPubMed
2.
Castro LR, Verde I, Cooper DM, Fischmeister R (2006) Cyclic guanosine monophosphate compartmentation in rat cardiac myocytes. Circulation 113:2221–2228CrossRefPubMed
3.
Dietrich A, Mederos Y, Schnitzler M, Gollasch M, Gross V, Storch U, Dubrovska G, Obst M, Yildirim E, Salanova B, Kalwa H, Essin K, Pinkenburg O, Luft FC, Gudermann T, Birnbaumer L (2005) Increased vascular smooth muscle contractility in TRPC6−/− mice. Mol Cell Biol 25:6980–6989CrossRefPubMed
4.
Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML (2009) Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway. Basic Res Cardiol 104:653–667CrossRefPubMed
5.
Errami M, Galindo CL, Tassa AT, Dimaio JM, Hill JA, Garner HR (2008) Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice. J Pharmacol Exp Ther 324:1196–1203CrossRefPubMed
6.
Feil R, Lohmann SM, de Jonge H, Walter U, Hofmann F (2003) Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res 93:907–916CrossRefPubMed
7.
Föller M, Feil S, Ghoreschi K, Koka S, Gerling A, Thunemann M, Hofmann F, Schuler B, Vogel J, Pichler B, Kasinathan RS, Nicolay JP, Huber SM, Lang F, Feil R (2008) Anemia and splenomegaly in cGKI-deficient mice. Proc Natl Acad Sci USA A105:6771–6776CrossRef
8.
Frey N, Mc Kinsey TA, Olson EN (2000) Decoding calcium signals involved in cardiac growth and function. Nat Med 6:1221–1227CrossRefPubMed
9.
Fujisaki H, Ito H, Hirata Y, Tanaka M, Hata M, Lin M, Adachi S, Akimoto H, Marumo F, Hiroe M (1995) Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. J Clin Invest 96:1059–1065CrossRefPubMed
10.
Grueter CE, Abiria SA, Dzhura I, Wu Y, Ham AJ, Mohler PJ, Anderson ME, Colbran RJ (2006) L-type Ca2+ channel facilitation mediated by phosphorylation of the beta subunit by CaMKII. Mol Cell 23:641–650CrossRefPubMed
11.
Hartmann J, Dragicevic E, Adelsberger H, Henning HA, Sumser M, Abramowitz J, Blum R, Dietrich A, Freichel M, Flockerzi V, Birnbaumer L, Konnerth A (2008) TRPC3 channels are required for synaptic transmission and motor coordination. Neuron 59:392–398CrossRefPubMed
12.
Hartmann M, Skryabin BV, Müller T, Gazinski A, Schröter J, Gassner B, Nikolaev VO, Bünemann M, Kuhn M (2008) Alternative splicing of the guanylyl cyclase-A receptor modulates atrial natriuretic peptide signaling. J Biol Chem 283:28313–28320CrossRefPubMed
13.
He LP, Hewavitharana T, Soboloff J, Spassova MA, Gill DL (2005) A functional link between store-operated and TRPC channels revealed by the 3, 5-bis(trifluoromethyl)pyrazole derivative, BTP2. J Biol Chem 280:10997–11006CrossRefPubMed
14.
Hercule HC, Tank J, Plehm R, Wellner M, da Costa Goncalves AC, Gollasch M, Diedrich A, Jordan J, Luft FC, Gross V (2007) Regulator of G protein signalling 2 ameliorates angiotensin II-induced hypertension in mice. Exp Physiol 92:1014–1022CrossRefPubMed
15.
Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH, Wyss JM, Mecham RP, Blumer KJ (2003) Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest 111:445–452PubMed
16.
17.
Hofmann T, Obukhov AG, Schaefer M, Harteneck C, Gudermann T, Schultz G (1999) Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 397:259–263CrossRefPubMed
18.
Holtwick R, van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M (2003) Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 111:1399–1407PubMed
19.
Katahira K, Mikami H, Ogihara T, Kohara K, Otsuka A, Kumahara Y, Khosla MC (1989) Synergism of intraventricular NaCl infusion and suppressor angiotensins in rats. Am J Physiol 256:H1–H8PubMed
20.
Kilic A, Velic A, De Windt LJ, Fabritz L, Voss M, Mitko D, Zwiener M, Baba HA, van Eickels M, Schlatter E, Kuhn M (2005) Enhanced activity of the myocardial Na+/H+ exchanger NHE-1 contributes to cardiac remodeling in atrial natriuretic peptide receptor-deficient mice. Circulation 112:2307–2311CrossRefPubMed
21.
Kim S, Iwao H (2000) Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev 52:11–34PubMed
22.
Kleinert HD, Maack T, Atlas SA, Januszewicz A, Sealey JE, Laragh JH (1984) Atrial natriuretic factor inhibits angiotensin-, norepinephrine-, and potassium-induced vascular contractility. Hypertension 6:I143–I147PubMed
23.
Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N (2001) Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 107:975–984CrossRefPubMed
24.
Kruse M, Schulze-Bahr E, Corfield V, Beckmann A, Stallmeyer B, Kurtbay G, Ohmert I, Schulze-Bahr E, Brink P, Pongs O (2009) Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I. J Clin Invest 119:2737–2744CrossRefPubMed
25.
Kuhn M (2004) Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol 99:76–8226CrossRefPubMed
26.
Kuhn M (2009) Function and dysfunction of mammalian membrane guanylyl cyclase receptors: lessons from genetic mouse models and implications for human diseases. Handb Exp Pharmacol. 191:47–69CrossRefPubMed
27.
Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, Izumi T, Takahashi N, Kawakami R, Tanimoto K, Nakagawa Y, Nakanishi M, Adachi Y, Garbers DL, Fukamizu A, Nakao K (2002) Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart. Circulation 106:1722–1728CrossRefPubMed
28.
Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A (1995) Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68CrossRefPubMed
29.
Maack T, Marion DN, Carnargo MJ, Kleinert HD, Laragh JH, Vaughan ED, Atlas SA (1984) Effects of auriculin (atrial natriuretic factor) on blood pressure, renal function, and the renin-aldosterone system in dogs. Am J Med 77:1069–1075CrossRefPubMed
30.
Maier LS (2009) Role of CaMKII for signaling and regulation in the heart. Front Biosci 14:486–496CrossRefPubMed
31.
Martin FL, Stevens TL, Cataliotti A, Schirger JA, Borgeson DD, Redfield MM, Luchner A, Burnett JC Jr (2005) Natriuretic and antialdosterone actions of chronic oral NEP inhibition during progressive congestive heart failure. Kidney Int 67:1723–1730CrossRefPubMed
32.
Mazzolai L, Nussberger J, Aubert J-H, Brunner DB, Gabbiani G, Brunne HR, Pedrazzini T (1998) Blood pressure-independent cardiac hypertrophy induced by locally activated renin-angiotensin system. Hypertension 31:1324–1330PubMed
33.
Mongillo M, Tocchetti CG, Terrin A, Lissandron V, Cheung YF, Dostmann WR, Pozzan T, Kass DA, Paolocci N, Houslay MD, Zaccolo M (2006) Compartmentalized phosphodiesterase-2 activity blunts beta-adrenergic cardiac inotropy via an NO/cGMP-dependent pathway. Circ Res 98:226–234CrossRefPubMed
34.
Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H (2006) TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J 25:5305–5316CrossRefPubMed
35.
Osei-Owusu P, Sun X, Drenan RM, Steinberg TH, Blumer KJ (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J Biol Chem 282:31656–31665CrossRefPubMed
36.
Ozaki M, Kawashima S, Yamashita T, Hirase T, Ohashi Y, Inoue N, Hirata K, Yokoyama M (2002) Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion. Circ J 66:851–856CrossRefPubMed
37.
Paradis P, Dali-Youcef N, Paradis FW, Thibault G, Nemer M (2000) Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc Natl Acad Sci USA 97:931–936CrossRefPubMed
38.
Pfeifer A, Klatt P, Massberg S, Ny L, Sausbier M, Hirneiss C, Wang GX, Korth M, Aszodi A, Andersson KE, Krombach F, Mayerhofer A, Ruth P, Fassler R, Hofmann F (1998) Defective smooth muscle regulation in cGMP kinase I-deficient mice. EMBO J 17:3045–3051CrossRefPubMed
39.
Sadoshima J, Izumo S (1993) Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res 73:413–423PubMed
40.
Saygili E, Rana OR, Meyer C, Gemein C, Andrzejewski MG, Ludwig A, Weber C, Schotten U, Krüttgen A, Weis J, Schwinger RH, Mischke K, Rassaf T, Kelm M, Schauerte P (2009) The angiotensin–calcineurin–NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes. Basic Res Cardiol 104:435–448CrossRefPubMed
41.
Seth M, Zhang ZS, Mao L, Graham V, Burch J, Stiber J, Tsiokas L, Winn M, Abramowitz J, Rockman HA, Birnbaumer L, Rosenberg P (2009) TRPC1 channels are critical for hypertrophic signaling in the heart. Circ Res 105:1023–1030CrossRefPubMed
42.
Surapisitchat J, Jeon KI, Yan C, Beavo JA (2007) Differential regulation of endothelial cell permeability by cGMP via phosphodiesterases 2 and 3. Circ Res 101:811–818CrossRefPubMed
43.
Takahahsi N, Saito Y, Kuwahara K, Harada M, Kishimoto I, Ogawa Y, Kawakami R, Nakagawa Y, Nakanishi M, Nakao K (2003) Angiotensin II-induced ventricular hypertrophy and extracellular signal-regulated kinase activation are suppressed in mice overexpressing brain natriuretic peptide in the circulation. Hypertens Res 26:847–853CrossRef
44.
Takimoto E, Belardi D, Tocchetti CG, Vahebi S, Cormaci G, Ketner EA, Moens AL, Champion HC, Kass DA (2007) Compartmentalization of cardiac beta-adrenergic inotropy modulation by phosphodiesterase type 5. Circulation 115:2159–2167CrossRefPubMed
45.
Takimoto E, Koitabashi N, Hsu S, Ketner EA, Zhang M, Nagayama T, Bedja D, Gabrielson KL, Blanton R, Siderovski DP, Mendelsohn ME, Kass DA (2009) Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 119:408–420PubMed
46.
Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME (2003) Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med 9:1506–1512CrossRefPubMed
47.
Tsai EJ, Kass DA (2009) Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 122:216–238CrossRefPubMed
48.
Valtcheva N, Nestorov P, Beck A, Russwurm M, Hillenbrand M, Weinmeister P, Feil R (2009) The commonly used cGMP-dependent protein kinase type I (cGKI) inhibitor Rp-8-Br-PET-cGMPS can activate cGKI in vitro and in intact cells. J Biol Chem 284:556–562CrossRefPubMed
49.
Weber S, Bernhard D, Lukowski R, Weinmeister P, Wörner R, Wegener JW, Valtcheva N, Feil S, Schlossmann J, Hofmann F, Feil R (2007) Rescue of cGMP kinase I knockout mice by smooth muscle specific expression of either isozyme. Circ Res 101:1096–1103CrossRefPubMed
50.
Westermann D, Riad A, Richter U, Jäger S, Savvatis K, Schuchardt M, Bergmann N, Tölle M, Nagorsen D, Gotthardt M, Schultheiss HP, Tschöpe C (2009) Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure. Basic Res Cardiol 104:499–509CrossRefPubMed
51.
Xie GX, Palmer PP (2007) How regulators of G protein signaling achieve selective regulation. J Mol Biol 366:349–365CrossRefPubMed
Metadata
Title
Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2
Authors
Michael Klaiber
Martin Kruse
Katharina Völker
Juliane Schröter
Robert Feil
Marc Freichel
Andrea Gerling
Susanne Feil
Alexander Dietrich
Juan Eduardo Camacho Londoño
Hideo A. Baba
Joel Abramowitz
Lutz Birnbaumer
Josef M. Penninger
Olaf Pongs
Michaela Kuhn
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Basic Research in Cardiology / Issue 5/2010
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-010-0098-z

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