Raised blood pressure, not renin–angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats

Bishop, June E.; Kiernan, L; Montgomery, Hugh; Gohlke, Peter; McEwan, Jean R.

doi:10.1016/s0008-6363(00)00063-8

Cited by 33 publications

(19 citation statements)

References 31 publications

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“…In both humans and animal models of hypertension, a primary cause of LV hypertrophy (LVH) is increased BP (29), and even modest reductions in this mechanical load normally lead to a decrease in LVH (30)(31)(32)(33)(34)(35)(36)(37). To determine whether chronic BP reduction alters the course of the naturally occurring cardiac hypertrophy in Npr1 -/-mice, we evaluated the effects of chronic administration of five commonly used antihypertensive agents given in the drinking water from the time of weaning at approximately 20 days of age until sacrifice at 4 months of age.…”

Section: Npra-null Mice Have Larger Than Normal Hearts Throughout Lifementioning

confidence: 99%

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Knowles

Esposito²,

Mao³

et al. 2001

J. Clin. Invest.

285

196

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IntroductionThe natriuretic peptide system plays a crucial role in blood pressure (BP) and blood volume (BV) homeostasis. Increases in atrial stretch trigger the release of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act through natriuretic peptide receptor A (NPRA) in the kidneys and vasculature to increase natriuresis, diuresis, and vasorelaxation (1-4).Elevations in circulating ANP and BNP are cardinal features of cardiac hypertrophy and heart failure in both humans and animal models (5-8), and induction of the ANP gene is one of the most robust responses to hypertrophic stimuli in the heart (9-12). Recent results suggest that these natriuretic peptides are not simply involved in BP and BV homeostasis but that they are also directly involved in moderating the cardiac growth response to hypertrophic stimuli. For example, the NPRA system has intrinsic growth inhibitory properties in noncardiac and cardiac cells in vitro (13). In endothelial and vascular smooth muscle cells (VSMCs), ANP is antimitogenic (14-17) and in cultured neonatal rat cardiomyocytes, ANP both attenuates the growth response to adrenergic stimuli (18) through a pathway that requires extracellular signal-related protein kinase (ERK) activation (19) and induces apoptosis (20). Furthermore, NPRA knockout mice (which have greatly attenuated responses to ANP and BNP) not only have increased BP, but also display marked cardiac hypertrophy and chamber dilatation by 3 months of age (21), whereas other mutant mice with similar increases in BP do not have this hypertrophic phenotype (22). These observations have led to the hypothesis that the NPRA signaling pathway plays an important autocrine role in the prevention of cardiac hypertrophy and heart failure beyond its effects on BP and BV regulation.To test the hypothesis that the NPRA pathway directly modulates the hypertrophic response we compare the response of Npr1 +/+ and Npr1 -/-mice to a pressure overload induced by transverse aortic constriction (TAC). We have also investigated the natural progression to cardiac hypertrophy that occurs in Npr1 -/-mice in the absence of TAC and the effects of chronic (3 months) BP normalization by enalapril, furosemide, hydralazine, or losartan. We conclude that the NPRA system indeed plays a primary role in moderating cardiac hypertrophy in vivo independently of its effects on BP regulation. Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1 -/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used t...

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Section: Npra-null Mice Have Larger Than Normal Hearts Throughout Lifementioning

confidence: 99%

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Knowles

Esposito²,

Mao³

et al. 2001

J. Clin. Invest.

285

196

View full text Add to dashboard Cite

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“…The reduction in circulating collagen markers during the first year of treatment was equal in the two groups. This suggests that cardiovascular fibrosis, assessed by circulating collagen markers, is related to haemodynamic load as previously shown in animals, 5,6 which, to some degree, is in contrast to the limited human data 8 stating that BP reduction without blocking the renin-angiotensin-aldosterone system is unable to reduce cardiac fibrosis and circulating collagen markers. However, the fact that the reduction in PICP/ICTP seen in patients receiving losartan was not associated with the reduction in BP may indicate a BP-independent mechanism of action for losartan on collagen synthesis 3 supporting the hypothesis of a superior effect of blockers of the renin-angiotensin-aldosterone system in reducing fibrosis.…”

Section: Discussionmentioning

confidence: 74%

“…4 Type I collagen is more stable with a slower turnover whereas type III collagen is more dynamic with a higher turnover which is reflected by more type I collagen in bone tissue and more type III collagen in the cardiovascular system. Myocardial fibrosis in transgenic (mRen2)27 rats was prevented by normalization of blood pressure (BP) 5 and postmyocardial infarction changes in type I collagen in the right ventricle were closely related to changes in diastolic BP, 6 indicating a causal relationship between haemodynamic stress, fibrosis and collagen markers. However, in other animal studies 7 and in essential hypertension the regression of myocardial fibrosis has been related to blockade of the renin-angiotensin-aldosterone system in addition to reduction in BP.…”

Section: Introductionmentioning

confidence: 99%

Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy

et al. 2005

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Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy, we measured sitting BP, serum collagen type I carboxy-terminal telopeptide (ICTP) reflecting degradation, procollagen type I carboxy-terminal propeptide (PICP) reflecting synthesis and LV mass by echocardiography after 2 weeks of placebo treatment and after 1 year of antihypertensive treatment with a losartan-or an atenolol-based regimen. Furthermore, we measured intima-media thickness of the common carotid arteries (IMT), minimal forearm vascular resistance (MFVR) by plethysmography and ambulatory 24-h BP in around half of the patients. At baseline, PICP/ICTP was positively related to IMT (r ¼ 0.24, Po0.05), MFVR men (r ¼ 0.35, Po0.01), 24-h systolic BP (r ¼ 0.24, Po0.05) and 24-h diastolic BP (r ¼ 0.22, Po0.05), but not to LV mass. After 1 year of treatment with reduction in systolic BP (175715 vs 151717 mmHg, Po0.001) and diastolic BP (9978 vs 8879 mmHg, Po0.001), ICTP was unchanged (3.771.4 vs 3.871.4 lg/l, NS) while PICP (121739 vs 102729 lg/l, Po0.001) decreased. The reduction in PICP/ICTP was related to the reduction in sitting diastolic BP (r ¼ 0.31, Po0.01) and regression of IMT (r ¼ 0.37, Po0.05) in patients receiving atenolol and to reduction in heart rate in patients receiving losartan (r ¼ 0.30, Po0.01). In conclusion, collagen markers reflecting net synthesis of type I collagen were positively related to vascular hypertrophy and BP load, suggesting that collagen synthesis in the vascular wall is increased in relation to high haemodynamic load in a reversible manner.

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“…23 In stark contrast, the AT 2 -deficient mice study by Senbonmatsu et al 16 implies that AT 2 activity is important for the left ventricular interstitial fibrotic response to pressure overload. A third view is that the cardiac AT 2 receptor stimulation has little or no influence on myocardial fibrosis 24,25 and that fibrosis more likely is related to the prevailing blood pressure. 24 In support of this view, the degree of postinfarct myocardial fibrosis in rats was attenuated by AT 1 blockade without any significant effects of added AT 2 blockade.…”

Section: At 2 Receptor and Cardiac Fibrosismentioning

confidence: 99%

“…A third view is that the cardiac AT 2 receptor stimulation has little or no influence on myocardial fibrosis 24,25 and that fibrosis more likely is related to the prevailing blood pressure. 24 In support of this view, the degree of postinfarct myocardial fibrosis in rats was attenuated by AT 1 blockade without any significant effects of added AT 2 blockade. 26 In humans, myocardial fibrosis can be regressed by angiotensin-converting enzyme (ACE) inhibition 27 that presumably reduces stimulation of both AT 1 and AT 2 receptors.…”

Section: At 2 Receptor and Cardiac Fibrosismentioning

confidence: 99%

Enhanced Angiotensin II Activity in Heart Failure

Opie

Sack

2001

Circulation Research

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Abstract-There are strong data favoring the pathogenic role of angiotensin II type 1 receptor (AT 1 ) activation with subsequent promotion of myocyte growth and cardiac fibrosis in the development of cardiac hypertrophy and heart failure. An emerging hypothesis suggests that the activity of the angiotensin II type 2 receptor (AT 2 ) may counterregulate AT 1 receptor effects during cardiac development and during the evolution of cardiac hypertrophy and heart failure. In this review, we examine the potential role of AT 2 activity in the context of this hypothesis. In contrast to the counterregulatory hypothesis, studies in mice with an overabundance of, or a deficiency in, the AT 2 receptor do not suggest that AT 2 signaling is essential for cardiac development. Moreover, the proposed antigrowth effects of AT 2 receptor signaling in pathological cardiac hypertrophy could not be shown in two mice models both deficient in AT 2 receptors. The role of AT 2 receptor signaling in cardiac fibrosis is, however, still debatable because of conflicting data in the same two studies. In angiotensin II-evoked apoptosis in cardiomyocytes, the proposed proapoptotic role of AT 2 activity could not be confirmed. Furthermore, in the progression from the bench to bedside, the results of two large clinical trials in heart failure, namely ELITE II and Val-HeFT, can be explained without ascribing a major protective role to the unopposed activity of the AT 2 receptor in the failing myocardium. In this review, we conclude that the collective evidence does not strongly support a net beneficial effect of AT 2 stimulation in the diseased myocardium.(Circ Res. 2001;88:654-658.)

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Raised blood pressure, not renin–angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats

Cited by 33 publications

References 31 publications

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A–deficient mice

Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy

Enhanced Angiotensin II Activity in Heart Failure

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