Angiotensin converting enzyme inhibitors block mitogenic signalling pathways in rat cardiac fibroblasts

Eickels, Martin van; Grohé, Christian; Löbbert, Kerstin; Stimpel, Michael; Vetter, Hans

doi:10.1007/pl00005366

Cited by 38 publications

(28 citation statements)

References 25 publications

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“…35 Furthermore, ACE inhibitors may elicit pleiotropic effects independently of local ACE inhibition 36 through direct regulation of cardiac Na ϩ /K ϩ pump activity 37 or mitogen activated protein kinase signal transduction. 38 One final consideration is that the whole heart is more complex than the isolated cardiomyocyte, and the multiple cell types and messenger systems that are present simultaneously are likely to modulate responses to different antihypertrophic agents. In the present study, any influences on hypertrophic markers and accumulation of cyclic GMP were assumed to be due to direct actions rather than secondary to a vasoactive action of the drug treatments, given that coronary flow varied little with different treatments in the present study.…”

Section: Discussionmentioning

confidence: 99%

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart

et al. 2002

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Abstract-The antihypertrophic action of angiotensin (Ang)-converting enzyme (ACE) inhibitors in the heart is attributed in part to potentiation of bradykinin. Bradykinin prevents hypertrophy of cultured cardiomyocytes by releasing nitric oxide (NO) from endothelial cells, which increases cardiomyocyte guanosine 3Ј5Ј-cyclic monophosphate (cyclic GMP). It is unknown whether cyclic GMP is essential for the action of bradykinin, or whether findings in isolated cardiomyocytes apply in whole hearts, in the presence of other cell types and mechanical/dynamic activity. We now examine the contribution of cyclic GMP to the antihypertrophic action of bradykinin in cardiomyocytes and perfused hearts. In adult rat isolated cardiomyocytes cocultured with bovine aortic endothelial cells, the inhibitory action of bradykinin (10 mol/L) against Ang II (1 mol/L)-induced 3 H]phenylalanine incorporation and atrial natriuretic peptide mRNA expression were prevented by bradykinin (100 nmol/L), the NO donor sodium nitroprusside (3 mol/L), and the ACE inhibitor ramiprilat (100 nmol/L). The acute antihypertrophic action of bradykinin was accompanied by increased left ventricular cyclic GMP, and the ramiprilat effect was attenuated by HOE 140 (1 mol/L, a B 2 -kinin receptor antagonist) or [1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (100 nmol/L). In conclusion, bradykinin exerts a direct inhibitory action against the acute hypertrophic response to Ang II in rat isolated hearts, and elevation of cardiomyocyte cyclic GMP may be an important antihypertrophic mechanism used by bradykinin and ramiprilat in the heart. Key Words: angiotensin-converting enzyme Ⅲ angiotensin II Ⅲ bradykinin Ⅲ cyclic GMP Ⅲ hypertrophy Ⅲ myocytes Ⅲ nitric oxide A ngiotensin-converting enzyme (ACE) inhibitors are often used to treat cardiac hypertrophy, 1 a significant cardiovascular risk factor in hypertensive patients. 2 The antihypertrophic action of ACE inhibitors in vivo is abolished by the B 2 -kinin receptor antagonist HOE 140, 3 indicating a significant contribution by bradykinin. In addition, B 2 -kinin receptor deficiency promotes the development of cardiac hypertrophy in vivo, 4 whereas kallikrein overexpression prevents cardiac growth. 5 However, the mechanism by which bradykinin counteracts hypertrophic stimuli in the heart is not fully understood. We have shown that bradykinin prevents hypertrophy of isolated cardiomyocytes by stimulating the release of NO from endothelial cells 6 and that this action is associated with elevation of cardiomyocyte cyclic GMP. 7 An analogue of cyclic GMP, 8-bromo-cyclic GMP, also prevents hypertrophy of isolated rat cardiomyocytes, 8 but whether stimulation of cyclic GMP is essential for the antihypertrophic action of bradykinin has not been addressed.Cardiomyocyte hypertrophy is characterized by increased protein synthesis and cell size and induction of the immediate early (eg, c-fos, c-jun, and c-myc) and fetal genes (eg, ␤-myosin heavy chain, skeletal ␣-actin, and atrial natriuretic peptide, ANP). 9 These cellular changes...

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Section: Discussionmentioning

confidence: 99%

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart

et al. 2002

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“…5,6,[21][22][23][24] Equal loading was checked by stripping and reprobing the membrane with troponin C. The following primary antibodies were used: ACE (BMA Biomedicals AG); ANP (Phoenix Pharmaceuticals Inc); angiotensin type 1 receptor (AT 1 R), ERK1/2, JNK, MKP1, p38-MAPK, phospho-JNK (Thr183/Tyr185), and troponin C (Santa Cruz Biotechnology Inc); and phospho-ERK1/2 (Thr202/Tyr204) and phospho-p-38 MAPK (Thr180/Tyr182) (New England Biolabs GmbH). Detection was performed with the enhanced chemiluminescence technique after incubation with a suitable secondary antibody coupled to horseradish peroxidase (ECL; Amersham Pharmacia Biotech).…”

Section: Immunoblot Analysismentioning

confidence: 99%

17β-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy

et al. 2001

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Background-Cardiac hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in men and in women. Epidemiological studies indicate that estrogen replacement therapy is cardioprotective; the mechanisms involved in this process, however, are poorly understood. We therefore studied the effect of 17␤-estradiol (E 2 ) on the development of pressure-overload hypertrophy. Methods and Results-Ovariectomized mice receiving E 2 or placebo underwent transverse aortic constriction (TAC) or sham operation. TAC led to a significant increase in ventricular mass compared with sham operation. E 2 treatment reduced cardiac hypertrophy by 31% and 26% compared with placebo 4 and 8 weeks after TAC, whereas it had no effect on the degree of pressure overload, as determined by hemodynamic measurements. Furthermore, E 2 blocked the increased phosphorylation of p38-mitogen-activated protein kinase (MAPK) observed in the placebo-treated animals with TAC. No differences were observed in the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 between the groups. E 2 had no effect on the expression of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor. Ventricular atrial natriuretic peptide (ANP) expression was detected only in the animals with TAC. Compared with placebo, E 2 treatment led to an increased expression of ANP in animals with pressure overload. Conclusions-Here, we show that E 2 attenuates the hypertrophic response to pressure overload in mice. This observation demonstrates that hormone replacement therapy with E 2 has direct effects on the heart and may be beneficial in the treatment of postmenopausal women to reduce cardiac hypertrophy. Key Words: hormones Ⅲ hypertrophy Ⅲ myocardium Ⅲ sex T he increase of left ventricular mass represents the structural mechanism of adaptation of the heart in response to pressure overload. The resulting left ventricular hypertrophy is an important negative predictor of cardiac morbidity and mortality and displays significant sex-based differences. 1,2 Estrogen is known to have multiple protective effects on the cardiovascular system. 3 The role of estrogen in the development of cardiac hypertrophy, however, is poorly understood. See p 1333We have shown previously that cardiac myocytes and cardiac fibroblasts contain both known estrogen receptor isoforms, called ␣ and ␤. 4 Via these receptors, estrogen can regulate the cardiac expression of endothelial and inducible NO synthase and connexin 43. 5 Estrogen also modulates the activity of the mitogen-activated protein kinase (MAPK) pathways in cardiac myocytes. 6 The MAPK signaling pathways consist of a sequence of successively acting kinases that ultimately result in the dual phosphorylation and activation of effector kinases such as p38-MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERKs), which subsequently phosphorylate a large array of targets, leading to altered gene expression patterns. 7 These signalin...

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“…Furthermore, myocardial inflammation as evidenced by polymorphonuclear leukocyte accumulation in ischemia/reperfusion tissue is markedly attenuated by prior p38 MAPK inhibition (Gao et al, 2002). Cell-based studies have reported that neurohormonal factors AngII, endothelin-1, and phenylephrine (Clerk et al, 1998;van Eickels et al, 1999), as well as ischemia (Mackay and Mochly-Rosen, 1999), are known to increase p38 MAPK activity. Furthermore, in myocytes transfected with mitogen-activated protein kinase kinase (MKK) 6, an upstream mediator of p38 MAPK, inflammatory markers are increased in response to cytokine simulation, an effect that is attenuated by p38 MAPK inhibition (Degousee et al, 2003).…”

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confidence: 99%

Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction

Kompa¹,

See²,

Lewis³

et al. 2008

J Pharmacol Exp Ther

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p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12-week p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt max ) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and ␣-smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after MI for 7 days showed similar improvements in fractional shortening, dP/dt max , LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy, with RWJ following tumor necrosis factor-␣ stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.Myocardial infarction (MI) results in progressive structural changes to the myocardium that progress to left ventricular (LV) dysfunction. As a compensatory measure to the decrease in cardiac output following MI, angiotensin II (AngII) and norepinephrine are activated to maintain cardiac function. However, long-term activation promotes vasoconstriction and pathological cardiac remodeling, leading to cardiac dysfunction. In addition, the release of proinflammatory cytokines contributes to the pathological process. Post-MI remodeling is characterized by LV dilatation, necrosis, and thinning of the LV wall, infarct expansion, hypertrophy of myocytes in the viable myocardium, and an increased accumulation of extracellular matrix material (fibrosis) within the infarcted and noninfarcted heart, impeding ventricular function (Tzanidis et al., 2001;Remme, 2003;See et al., 2004).Evidence indicates that p38 mitogen-activated protein kinase (p38 MAPK) may be a common intracellular signaling pathway involved in cardiac remodeling, activated by

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Angiotensin converting enzyme inhibitors block mitogenic signalling pathways in rat cardiac fibroblasts

Cited by 38 publications

References 25 publications

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart

Acute Antihypertrophic Actions of Bradykinin in the Rat Heart

17β-Estradiol Attenuates the Development of Pressure-Overload Hypertrophy

Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction

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