Angiotensin II Type 1 Receptor Blocker Attenuates Myocardial Remodeling and Preserves Diastolic Function in Diabatic Heart

Tsutsui, Hiroyuki; Matsushima, Shouji; Kinugawa, Shintaro; Ide, Tomomi; Inoue, Naoki; Ohta, Yukihiro; Yokota, Takashi; Hamaguchi, Sanae; Sunagawa, Kenji

doi:10.1291/hypres.30.439

Cited by 65 publications

(53 citation statements)

References 40 publications

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“…As expected, CTGF expression, which is known to be angiotensin-II driven, was downregulated to a similar degree by both the QHI and LOS treatment groups, despite the blood pressure difference between these two groups. [34][35][36] The combined DXQ treatment group did not show such effects, showing the angiotensin-II doseinhibition effect. Interestingly, we have found a downregulation of the thioredoxininteracting protein (Txnip) in early LVH but not in late LVH.…”

Section: Proliferation/cell Growthmentioning

confidence: 86%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

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Section: Proliferation/cell Growthmentioning

confidence: 86%

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

et al. 2009

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“…However, more markers of specific intracellular AT1R downstream signaling need to be established to support this hypothesis. A recent study by Tsutsui et al (2007) reports on the beneficial effects of the AT1R blocker candesartan on diastolic dysfunction as well as myocardial interstitial fibrosis and TGF-b-CTGF expression in diabetic mice. This study supports our findings on the central role of AngII in mediating the structural and functional abnormalities of the diabetic heart, in addition to the previously described role of increased oxidative stress in diabetic complications in general (Griendling et al 1994) and the diabetic heart in particular (Fiordaliso et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Early blood pressure-independent cardiac changes in diabetic rats

Landau¹,

Chayat

Zucker³

et al. 2008

Journal of Endocrinology

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Cardiac remodeling is a key event in both diabetic and hypertensive heart diseases. In the present study, we investigated early myocardial changes in an animal model, the male Sabra rat model (SBH/y) of salt-induced hypertension-rendered diabetic with streptozotocin. Control non-diabetic (C), diabetic (D), and D or C rats made hypertensive by salt loading (DS or CS) were studied after 6 weeks. M-mode echocardiography revealed that left ventricular internal dimension during diastole and systole were significantly increased in D and DS, but not in C or CS. Concurrently, we found in D and DS an increase in cardiac b-myosin heavy chain, atrial natriuretic peptide, skeletal a-actin mRNA, type III collagen, and transforming growth factor-b.Myocardial angiotensin-converting enzyme (ACE) mRNA levels were increased while ACE2 mRNA levels were decreased in both D and DS groups. Cardiac angiotensin-1 (AT1) receptor protein levels were unchanged but the levels of phosphorylated (p) ERK and Jun-NH 2 -protein kinase (JNK) were increased in D and DS. In conclusion, we detected early cardiac changes in diabetic rats that were unrelated to hypertension. The increase in ACE, the decrease in ACE2, and the increase in cardiac pERK and pJNK suggest an increase in free angiotensin II and AT1R signaling in the diabetic myocardium as a possible mechanism contributing to cardiac remodeling in diabetes.

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“…44 Duisters et al 45 reported that CTGF is regulated by two major cardiac microRNAs, which were downregulated in several models of cardiac hypertrophy and heart failure. Recently, Panek et al 46 reported that cardiomyocyte-specific CTGF transgenic mice developed cardiac dysfunction but did not develop cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

et al. 2010

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Connective tissue growth factor (CTGF) is a secreted protein that regulates fibrosis. We hypothesized that CTGF is induced in a pressure-overloaded (PO) heart and that blocking the angiotensin II type 1 receptor would reduce CTGF expression. Accordingly, we administered olmesartan and compared its effects with other antihypertensive drugs in a PO heart. CTGF induction was determined in a rat PO model, and olmesartan, hydralazine or saline was continuously administered. The effects of olmesartan on CTGF induction, myocyte hypertrophy and fibrosis were evaluated. The effect of olmesartan on cardiac function was also examined in CTGF-and transforming growth factor-beta 1 (TGF-b1)-infused rats. CTGF was increased in the PO heart 3 days after aortic banding and was markedly distributed around the perivascular fibrotic area. After 28 days, blood pressure was not significantly different in the olmesartan and hydralazine groups, but olmesartan treatment reduced CTGF distribution in PO hearts. Olmesartan was associated with a significantly reduced myocyte hypertrophy index (4.77 ± 0.48 for olmesartan and 6.05 ± 1.45 for saline, Po0.01), fibrosis area (32.0 ± 15.5% compared with the saline group, Po0.05) and serum TGF-b1 level (62.6±10.6 ng ml À1 for olmesartan and 84.4±7.2 ng ml À1 for hydralazine, Po0.05). In addition, cardiac function was significantly preserved in the olmesartan group compared with the saline group. Finally, olmesartan ameliorated the cardiac dysfunction in CTGF-and TGF-b1-infused rats. Olmesartan attenuated CTGF induction, reduced perivascular fibrosis and ameliorated cardiac dysfunction in a PO heart. Our results provide insight into the beneficial effects of olmesartan on PO hearts, independent of blood-pressure lowering.

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Angiotensin II Type 1 Receptor Blocker Attenuates Myocardial Remodeling and Preserves Diastolic Function in Diabatic Heart

Abstract: Blockade of the renin-angiotensin system reduces cardiovascular morbidity and mortality in diabetic

Cited by 65 publications

References 40 publications

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies

Early blood pressure-independent cardiac changes in diabetic rats

Connective tissue growth factor induction in a pressure-overloaded heart ameliorated by the angiotensin II type 1 receptor blocker olmesartan

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