nach oben

Erschienen in:

01.09.2009 | Original Contribution

Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure

verfasst von: Dirk Westermann, Alexander Riad, Utz Richter, Sebastian Jäger, Konstantinos Savvatis, Mirjam Schuchardt, Nora Bergmann, Markus Tölle, Dirk Nagorsen, Michael Gotthardt, Heinz-Peter Schultheiss, Carsten Tschöpe

Erschienen in: Basic Research in Cardiology | Ausgabe 5/2009

Einloggen, um Zugang zu erhalten

Abstract

Background

Diastolic heart failure is a rising problem with a high incidence and similar mortality and morbidity compared to patients with systolic heart failure. Nevertheless, the underlying pathophysiology is still debated.

Aim

We investigated the effect of pharmacological enhancement of endothelial nitric oxide synthase (eNOS) on experimental diastolic heart failure (DHF).

Methods

DHF was induced in 60 DAHL salt-sensitive rats by salt diet in 8-week-old animals. 30 were treated with the eNOS enhancer AVE3085 (DHFeNOS) and 30 with placebo (DHF). Rats with normal salt intake served as controls.

Results and conclusion

Diastolic dysfunction with increased diastolic stiffness constant and increased left ventricular (LV) pressure was analyzed by invasive pressure–volume loop measurements in the DHF group compared to controls. Cardiac hypertrophy as indicated by LV mass measurements by echocardiography, and increased cardiac collagen content as measured by immunohistochemistry were associated with an increased activation state of calcineurin, AKT, ERK½, but not JNK and p38 kinases. Titin isoforms were not altered in this model of DHF. Treatment with AVE3085 significantly increased eNOS mRNA and protein levels in the cardiac tissue and decreases NAD(P)H oxidase subunits p22phox and gp91phox. Diastolic dysfunction was attenuated and cardiac hypertrophy and fibrosis were improved in comparison with untreated DHF animals. This was associated with a normalized activation state of calcineurin, AKT and ERK½. Therefore, we suggest that targeting the NO system might yield a future therapeutic aim for the treatment of DHF.

Bueno OF, De Windt LJ, Tymitz KM, Witt SA, Kimball TR, Klevitsky R, Hewett TE, Jones SP, Lefer DJ, Peng CF, Kitsis RN, Molkentin JD (2000) The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. Embo J 19:6341–6350PubMedCrossRef

Chen X, Niroomand F, Liu Z, Zankl A, Katus HA, Jahn L, Tiefenbacher CP (2006) Expression of nitric oxide related enzymes in coronary heart disease. Basic Res Cardiol 101:346–353PubMedCrossRef

De Keulenaer GW, Brutsaert DL (2007) Systolic and diastolic heart failure: different phenotypes of the same disease? Eur J Heart Fail 9:136–143PubMedCrossRef

Devereux RB, Roman MJ, de Simone G, O’Grady MJ, Paranicas M, Yeh JL, Fabsitz RR, Howard BV (1997) Relations of left ventricular mass to demographic and hemodynamic variables in American Indians: the strong heart study. Circulation 96:1416–1423PubMed

Doi R, Masuyama T, Yamamoto K, Doi Y, Mano T, Sakata Y, Ono K, Kuzuya T, Hirota S, Koyama T, Miwa T, Hori M (2000) Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J Hypertens 18:111–120PubMedCrossRef

Fukuta H, Sane DC, Brucks S, Little WC (2005) Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation 112:357–363PubMedCrossRef

Gonon AT, Bulhak A, Labruto F, Sjoquist PO, Pernow J (2007) Cardioprotection mediated by rosiglitazone, a peroxisome proliferator-activated receptor gamma ligand, in relation to nitric oxide. Basic Res Cardiol 102:80–89PubMedCrossRef

Guo P, Nishiyama A, Rahman M, Nagai Y, Noma T, Namba T, Ishizawa M, Murakami K, Miyatake A, Kimura S, Mizushige K, Abe Y, Ohmori K, Kohno M (2006) Contribution of reactive oxygen species to the pathogenesis of left ventricular failure in Dahl salt-sensitive hypertensive rats: effects of angiotensin II blockade. J Hypertens 24:1097–1104PubMedCrossRef

Hogg K, Swedberg K, McMurray J (2004) Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol 43:317–327PubMedCrossRef

10.

Ito N, Ohishi M, Yamamoto K, Tatara Y, Shiota A, Hayashi N, Komai N, Yanagitani Y, Rakugi H, Ogihara T (2007) Renin-angiotensin inhibition reverses advanced cardiac remodeling in aging spontaneously hypertensive rats. Am J Hypertens 20:792–799PubMedCrossRef

11.

Kass DA, Takimoto E, Nagayama T, Champion HC (2007) Phosphodiesterase regulation of nitric oxide signaling. Cardiovasc Res 75:303–314PubMedCrossRef

12.

Kim S, Yoshiyama M, Izumi Y, Kawano H, Kimoto M, Zhan Y, Iwao H (2001) Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure. Circulation 103:148–154PubMed

13.

Klotz S, Hay I, Zhang G, Maurer M, Wang J, Burkhoff D (2006) Development of heart failure in chronic hypertensive Dahl rats: focus on heart failure with preserved ejection fraction. Hypertension 47:901–911PubMedCrossRef

14.

Lam CS, Roger VL, Rodeheffer RJ, Bursi F, Borlaug BA, Ommen SR, Kass DA, Redfield MM (2007) Cardiac structure and ventricular–vascular function in persons with heart failure and preserved ejection fraction from Olmsted County, Minnesota. Circulation 115:1982–1990PubMedCrossRef

15.

Lamberts RR, Vaessen RJ, Westerhof N, Stienen GJ (2007) Right ventricular hypertrophy causes impairment of left ventricular diastolic function in the rat. Basic Res Cardiol 102:19–27PubMedCrossRef

16.

Landmesser U, Engberding N, Bahlmann FH, Schaefer A, Wiencke A, Heineke A, Spiekermann S, Hilfiker-Kleiner D, Templin C, Kotlarz D, Mueller M, Fuchs M, Hornig B, Haller H, Drexler H (2004) Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 110:1933–1939PubMedCrossRef

17.

Liang Q, Molkentin JD (2003) Redefining the roles of p38 and JNK signaling in cardiac hypertrophy: dichotomy between cultured myocytes and animal models. J Mol Cell Cardiol 35:1385–1394PubMedCrossRef

18.

Lopez B, Gonzalez A, Querejeta R, Larman M, Diez J (2006) Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 48:89–96PubMedCrossRef

19.

Martos R, Baugh J, Ledwidge M, O’Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K (2007) Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 115:888–895PubMedCrossRef

20.

Matsui H, Shimosawa T, Uetake Y, Wang H, Ogura S, Kaneko T, Liu J, Ando K, Fujita T (2006) Protective effect of potassium against the hypertensive cardiac dysfunction: association with reactive oxygen species reduction. Hypertension 48:225–231PubMedCrossRef

21.

Molkentin JD (2004) Calcineurin–NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res 63:467–475PubMedCrossRef

22.

Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259PubMedCrossRef

23.

Paulus WJ (2000) Beneficial effects of nitric oxide on cardiac diastolic function: ‘the flip side of the coin’. Heart Fail Rev 5:337–344PubMedCrossRef

24.

Paulus WJ, Frantz S, Kelly RA (2001) Nitric oxide and cardiac contractility in human heart failure: time for reappraisal. Circulation 104:2260–2262PubMed

25.

Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL (2007) How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 28:2539–2550PubMedCrossRef

26.

Paulus WJ, Vantrimpont PJ, Shah AM (1994) Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Assessment by bicoronary sodium nitroprusside infusion. Circulation 89:2070–2078PubMed

27.

Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA (2005) Age- and gender-related ventricular-vascular stiffening: a community-based study. Circulation 112:2254–2262PubMedCrossRef

28.

Riad A, Westermann D, Van Linthout S, Mohr Z, Uyulmaz S, Becher PM, Rutten H, Wohlfart P, Peters H, Schultheiss HP, Tschope C (2008) Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes. Diabetologia 51:2325–2332PubMedCrossRef

29.

Ruetten H, Dimmeler S, Gehring D, Ihling C, Zeiher AM (2005) Concentric left ventricular remodeling in endothelial nitric oxide synthase knockout mice by chronic pressure overload. Cardiovasc Res 66:444–453PubMedCrossRef

30.

Sakata Y, Chancey AL, Divakaran VG, Sekiguchi K, Sivasubramanian N, Mann DL (2008) Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor. Basic Res Cardiol 103:60–68PubMedCrossRef

31.

Sasaki K, Heeschen C, Aicher A, Ziebart T, Honold J, Urbich C, Rossig L, Koehl U, Koyanagi M, Mohamed A, Brandes RP, Martin H, Zeiher AM, Dimmeler S (2006) Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy. Proc Natl Acad Sci USA 103:14537–14541PubMedCrossRef

32.

Schott P, Asif AR, Graf C, Toischer K, Hasenfuss G, Kogler H (2008) Myocardial adaptation of energy metabolism to elevated preload depends on calcineurin activity: a proteomic approach. Basic Res Cardiol 103:232–243PubMedCrossRef

33.

Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11:214–222PubMedCrossRef

34.

Takimoto E, Kass DA (2007) Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49:241–248PubMedCrossRef

35.

Tang M, Zhang W, Lin H, Jiang H, Dai H, Zhang Y (2007) High glucose promotes the production of collagen types I and III by cardiac fibroblasts through a pathway dependent on extracellular-signal-regulated kinase 1/2. Mol Cell Biochem 301:109–114PubMedCrossRef

36.

Tribouilloy C, Rusinaru D, Mahjoub H, Souliere V, Levy F, Peltier M, Slama M, Massy Z (2008) Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study. Eur Heart J 29:339–347PubMedCrossRef

37.

Tschope C, Bock CT, Kasner M, Noutsias M, Westermann D, Schwimmbeck PL, Pauschinger M, Poller WC, Kuhl U, Kandolf R, Schultheiss HP (2005) High prevalence of cardiac parvovirus B19 infection in patients with isolated left ventricular diastolic dysfunction. Circulation 111:879–886PubMedCrossRef

38.

van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113:1966–1973PubMedCrossRef

39.

Warren CM, Jordan MC, Roos KP, Krzesinski PR, Greaser ML (2003) Titin isoform expression in normal and hypertensive myocardium. Cardiovasc Res 59:86–94PubMedCrossRef

40.

Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C (2008) Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation 117:2051–2060PubMedCrossRef

41.

Westermann D, Knollmann BC, Steendijk P, Rutschow S, Riad A, Pauschinger M, Potter JD, Schultheiss HP, Tschope C (2006) Diltiazem treatment prevents diastolic heart failure in mice with familial hypertrophic cardiomyopathy. Eur J Heart Fail 8:115–121PubMedCrossRef

42.

Westermann D, Riad A, Lettau O, Roks A, Savvatis K, Becher PM, Escher F, Jan Danser AH, Schultheiss HP, Tschope C (2008) Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. Hypertension 52:1068–1075PubMedCrossRef

43.

Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646PubMedCrossRef

44.

Westermann D, Van Linthout S, Dhayat S, Dhayat N, Escher F, Bucker-Gartner C, Spillmann F, Noutsias M, Riad A, Schultheiss HP, Tschope C (2007) Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes 56:1834–1841PubMedCrossRef

45.

Wilkins BJ, Dai YS, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molkentin JD (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118PubMedCrossRef

46.

Wohlfart P, Xu H, Endlich A, Habermeier A, Closs EI, Hubschle T, Mang C, Strobel H, Suzuki T, Kleinert H, Forstermann U, Ruetten H, Li H (2008) Antiatherosclerotic effects of small-molecular-weight compounds enhancing endothelial nitric-oxide synthase (eNOS) expression and preventing eNOS uncoupling. J Pharmacol Exp Ther 325:370–379PubMedCrossRef

47.

Zhang C (2008) The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 103:398–406PubMedCrossRef

48.

Zile MR, Baicu CF, Gaasch WH (2004) Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 350:1953–1959PubMedCrossRef

Titel: Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure
verfasst von: Dirk Westermann
Alexander Riad
Utz Richter
Sebastian Jäger
Konstantinos Savvatis
Mirjam Schuchardt
Nora Bergmann
Markus Tölle
Dirk Nagorsen
Michael Gotthardt
Heinz-Peter Schultheiss
Carsten Tschöpe
Publikationsdatum: 01.09.2009
Verlag: D. Steinkopff-Verlag
Erschienen in: Basic Research in Cardiology / Ausgabe 5/2009
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-009-0014-6

Neu im Fachgebiet Kardiologie

19.04.2024 | Vorhofflimmern | Nachrichten

Update Kardiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Enhancement of the endothelial NO synthase attenuates experimental diastolic heart failure

Abstract

Background

Aim

Methods

Results and conclusion

Neu im Fachgebiet Kardiologie

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Sind Betablocker auch für ältere herzschwache Personen nützlich?

Stillende Frauen haben geringeres kardiovaskuläres Risiko

Update Kardiologie

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Springer Medizin

Abstract

Background

Aim

Methods

Results and conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2009

Regional, age-dependent, and genotype-dependent differences in ventricular action potential duration and activation time in 410 Langendorff-perfused mouse hearts

The metabolic modulators, Etomoxir and NVP-LAB121, fail to reverse pressure overload induced heart failure in vivo

Bone marrow-derived cells are not involved in reendothelialized endothelium as endothelial cells after simple endothelial denudation in mice

Ischemic postconditioning: experimental models and protocol algorithms

Diastolic heart failure: a misNOmer

Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein?

Neu im Fachgebiet Kardiologie

Parodontalbehandlung verbessert Prognose bei Katheterablation

Antihypertensiva schützen auch alte Menschen noch vor Demenz

Sind Betablocker auch für ältere herzschwache Personen nützlich?

Stillende Frauen haben geringeres kardiovaskuläres Risiko

Update Kardiologie