Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II

Seccia, Teresa Maria; Belloni, Anna S.; Kreutz, Reinhold; Paul, Martin; Nussdorfer, Gastone G.; Pessina, Achille C.; Rossi, Gian Paolo

doi:10.1016/s0735-1097(02)02860-7

Cited by 90 publications

(72 citation statements)

References 37 publications

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“…8 Also, this dose resembles that used by other authors. 26,11,27 Our present results are in agreement with our previous findings that nonselective ET receptor blockade with bosentan improved survival rate but had no effect on the course of hypertension in homozygous 8 or heterozygous TGR. 11,10 Similarly, Karam et al 28 also found that the renoprotective actions of bosentan were independent of any BP-lowering effect.…”

Section: Discussionsupporting

confidence: 93%

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

et al. 2005

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Abstract-We have recently found that nonselective endothelin ET A /ET B receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Key Words: hypertension Ⅲ kidney Ⅲ antihypertensive drugs Ⅲ end-organ damage Ⅲ systolic Ⅲ experimental models E ndothelin-1 (ET-1) has been described as one of the most powerful vasoconstrictors 1,2 that also plays a role in the regulation of renal hemodynamics and salt and water excretion. 3 Moreover, numerous studies have shown that the ET system plays an important role in the pathogenesis of saltsensitive models of hypertension and in associated end-organ damage. 4 The nephroprotective effect of ET receptor blockade in these models is comparable with blockade of the renin-angiotensin system. 5 The beneficial effects of ET receptor blockers in modulating target-organ damage arises from their antiproliferative actions. 6 There is, however, a large discrepancy in the effect of ET between various models of hypertension. Animal models with exogenously administered angiotensin II (ANG II) exhibit an ET-dependent component, whereas hypertensive models with endogenously enhanced production of ANG II do not. 7 In our previous study, we showed that bosentan treatment substantially improved the survival rate in homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene fed either normal-salt or high-salt diet without blood pressure (BP)-lowering effect. 8 Whereas the protective action of nonselective ET blockade has attracted much attention in homozygous TGR, 8,9 there is no information available concerning the effect of selective ET A blockade on the course of hypertension and end-organ damage in homozygous TGR and little information is available in heterozygous animals. 10,11 It is well-known that young animals are more susceptible to various hypertensive stimuli 12 and also that interventions made in these early periods are more effective than when adopted lately in the life. 13 However, in Dahl-sensitive rats it has been shown that ET A receptor blockade was efficient in adult but not in young animals. 14 The transgenic hypertensive TGR(mRen2)27 rat model 15 is a valuable monogenetic model of renin-dependent (and thus ANG II-dependent) hypertension, which exhibits functional and structural changes of the kidney usually found in hyper-

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Section: Discussionsupporting

confidence: 93%

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

et al. 2005

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“…Whether RVH that occurs during chronic hypoxia results from ET-1 synthesis in RV cardiomyocytes has yet to be determined. Interestingly, LVH in heterozygous male Ren2 rats is ET-1 dependent in older (12-to 16-wk-old) rats and younger rats on a high-salt diet, but not in younger (6-to 9-wk-old) rats on a normal-salt diet (50,56,61), similar to those used in the present study. We speculate that RVH in heterozygous male Ren2 rats is more dependent on the endothelin system than LVH and that the endothelin system in the RV is not fully activated in younger rats.…”

Section: Methodological Considerationssupporting

confidence: 62%

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

DeMarco

Habibi

Whaley‐Connell

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Dellsperger KC. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 294: H2659-H2668, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00953.2007.-The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22 phox , and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P Ͻ 0.05). Tempol decreased RVSP (P Ͻ 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22 phox , and Rac-1 protein expression, and ROS in Ren2 rats (P Ͻ 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P Ͻ 0.001) and luminal surface area was 54% less (P Ͻ 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P Ͻ 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling. renin; angiotensin II; NADPH oxidase CARDIOVASCULAR GENERATION of reactive oxygen species (ROS), such as superoxide and H 2 O 2 , has been implicated in the pathogenesis of hypertension, cardiac hypertrophy, pulmonary hypertension (PH), and heart failure (7). Molecular complexes known to generate superoxide within vascular endothelial and smooth muscle cells (SMC) include the NADPH oxidases (18), xanthine oxidase (32), the mitochondrial transport chain, and uncoupled nitric oxide synthase (NOS) (10,19). NADPH oxidase is a major source of ROS in the vasculature and is activated by hormones, growth factors, cytokines, and shear stress (16). An important stimulus for NADPH oxidase-generated ROS is ANG II. In fact, many of the deleterious effects of ANG II on vascular structure and function are mediated by ROS generation (16,73). ANG II causes rapid induction of NADPH oxidase-dependent superoxide synthesis via PKC (15) and more prolonged stimulation via transactivation of growth factors (62, 69). ANG II also causes redox-sensitive xanthine oxidase activation and endothelial N...

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“…7). Periarterial fibrosis has been reported in these transgenic rats as young as 8 -9 wk of age (28,31), and extensive interstitial fibrosis and scarring have been reported in 13-to 14-wk-old Ren2 rats (23). The myocardium of 10-to 11-wk-old Ren2 male rats studied here exhibited modest interstitial fibrosis.…”

Section: Discussionsupporting

confidence: 46%

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

DeMarco

Johnson

Habibi

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-␥ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-␥ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg·kg Ϫ1 ·day Ϫ1 ), olmesartan (2.5 mg·kg Ϫ1 ·day Ϫ1 ), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt max-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P Ͻ 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation. oxidative stress; left ventricular hypertrophy; peroxisome proliferatoractivated receptor-␥; Janus-activated kinase 2; AMP-activated protein kinase NUMEROUS REPORTS have demonstrated a seminal role for ANG II and the associated generation of ROS via NADPH oxidase in the development of myocardial remodeling and that angiotensin type 1 receptor (AT 1 R) blockade improves myocardial remodeling, hypertrophy, and ventricular compliance (4, 5, 31). A molecular modeling study (4) demonstrated a structural similarity between the AT 1 R blocker telmisartan and the peroxisome proliferator-activated receptor (PPAR)-␥ agonists pioglitazone and rosiglitazone. Telmisartan, to a greater extent than other angiotensin receptor blockers (ARB), acts as a partial agonist of PPAR-␥ independently of AT 1 R-blocking effects (4, 27). PPAR-␥ agonism improves insulin sensitivity and inhibits vascular oxidative stress and inflammation (11). In this regard, telmisartan reduces glucose, insulin, and triglyceride levels in a rat model of high-fat diet-induced insulin resistance (4).Some evidence suggests that PPAR-␥ a...

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Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II

Cited by 90 publications

References 37 publications

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

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