Angiotensin Type 1 Receptor Blockade Prevents Cardiac Remodeling in Mice with Pregnancy-Associated Hypertension

Sakairi, Akira; Ishida, Junji; Honjo, Kaori; Inaba, Saki; Nakamura, Shoko; Sugiyama, Fumihiro; Yagami, Ken‐ichi; Fukamizu, Akiyoshi

doi:10.1291/hypres.31.2165

Cited by 14 publications

(13 citation statements)

References 56 publications

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Section: H Ypertension That Results In Left Ventricular (Lv) Hyper-mentioning

confidence: 97%

“…Investigations into the role of cardiomyocyte apoptosis in the development of LV hypertrophy in animal models produced discrepant results. Some research groups found that cardiomyocyte apoptosis increased in LV hypertrophy and inhibition of apoptosis could alleviate ventricular hypertrophy, 4,5) whereas other research teams found contrary results.6) Further studies to elucidate the relationship between cardiomyocyte apoptosis and hypertensive LV hypertrophy are therefore required.Connective tissue growth factor (CTGF), a newly defined cell factor which takes part in regulation of the secretion of extracellular matrix by fibroblasts, has important roles in the fibrosis of various organs, including the liver, kidney, and heart ventricles. 7,8) Recent studies have indicated that inhibition of expression of CTGF protein may be a therapeutic target of myocardial fibrosis.…”

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confidence: 99%

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Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

Zhao

Zhang

et al. 2010

Int. Heart J.

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SummaryStatins improve left ventricular (LV) remodeling in spontaneously hypertensive rats (SHRs). This study was designed to investigate the effects of atorvastatin administered in the early stage on LV remodeling in SHRs, and to explore the underlying mechanisms.Sixteen male 8-week-old SHRs were randomized to receive distilled water (SHR-DW) or atorvastatin (SHR-ATV) for 12 weeks. Age-matched male Wistar-Kyoto (WKY) rats gavaged with distilled water served as controls. LV remodeling was evaluated, myocardial CTGF expression levels were detected using Western blotting, and cardiomyocyte apoptosis was detected with the TUNEL method.Compared with WKY and SHR-DW, atorvastatin treatment significantly decreased systolic blood pressure in SHRs; atorvastatin significantly inhibited LV remodeling, as indicated by the reduced LV weight/body weight ratio (SHR-ATV: 4.0 ± 0.4 versus SHR-DW: 4.7 ± 0.4 mg/g, P < 0.05), cardiomyocyte diameter (SHR-ATV: 16.2 ± 2.8 versus SHR-DW: 19.0 ± 1.0 μm, P < 0.05), and interstitial fibrosis (SHR-ATV: 3.3 ± 2.1 versus SHR-DW: 4.5 ± 1.8%, P < 0.05). Compared with WKY, myocardial CTGF expression was significantly increased and cardiomyocyte apoptosis decreased in SHRs. Compared with the SHR-DW group, atorvastatin treatment significantly inhibited myocardial CTGF expression (SHR-ATV: 0.69 ± 0.21 versus SHR-DW: 1.12 ± 0.27, P < 0.05) and induced cardiomyocyte apoptosis in SHRs (SHR-ATV: 5.2 ± 0.6 versus SHR-DW: 1.9 ± 0.3%, P < 0.05).The results indicate that early-stage administration of atorvastatin effectively prevented LV remodeling in SHRs, and that inhibition of myocardial CTGF expression and induction of cardiomyocyte apoptosis may be the underlying mechanisms. ( ) contributed to the development and evolution of LV remodeling in hypertensive models. Investigations into the role of cardiomyocyte apoptosis in the development of LV hypertrophy in animal models produced discrepant results. Some research groups found that cardiomyocyte apoptosis increased in LV hypertrophy and inhibition of apoptosis could alleviate ventricular hypertrophy, 4,5) whereas other research teams found contrary results.6) Further studies to elucidate the relationship between cardiomyocyte apoptosis and hypertensive LV hypertrophy are therefore required.Connective tissue growth factor (CTGF), a newly defined cell factor which takes part in regulation of the secretion of extracellular matrix by fibroblasts, has important roles in the fibrosis of various organs, including the liver, kidney, and heart ventricles. 7,8) Recent studies have indicated that inhibition of expression of CTGF protein may be a therapeutic target of myocardial fibrosis. 9,10) Several studies confirmed the beneficial effects of statins on inhibiting hypertension-induced LV remodeling. Simvastatin mitigates hypertension-induced myocardial fibrosis through down-regulation of myocardial CTGF. 11)In rats with pulmonary arterial hypertension, simvastatin prevents and, to some extent, reverses vascular remodeling via down-regulation of CTGF gene expre...

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Section: H Ypertension That Results In Left Ventricular (Lv) Hyper-mentioning

confidence: 97%

mentioning

confidence: 99%

Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

Zhao

Zhang

et al. 2010

Int. Heart J.

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“…These data show evidence of the deteriorative action of Ang II on the pathogenesis of pre-eclampsia; however, it has been difficult to elucidate the pathophysiological significance of aberrant RAS activation in the human case, because of the contraindication of RAS inhibition during pregnancy (24,25). Previously, using mice with PAH, we demonstrated the importance of RAS activation with enhanced AT1 signaling in the pathogenesis of hypertension during pregnancy (18,21). Additionally, the short-term administration of an ARB for the last 2 days of pregnancy in mice with PAH also recovered IUGR (18); however, the therapeutic but not preventive effect of RAS suppression on extensive PAH pathology was not clarified.…”

Section: Discussionmentioning

confidence: 63%

“…Mice with PAH have also been shown to exhibit proteinuria and cardiac hypertrophy, and fetuses at term have shown severe intrauterine growth retardation (IUGR) with placental morphological changes (18)(19)(20). We have previously demonstrated the importance of the AT1 receptor in the pathogenesis of hypertension during pregnancy using mice with PAH (18,21); however, the beneficial effect of RAS suppression during the advanced stages of PAH was not fully elucidated. In the present study, we administered olmesartan (Olm), an angiotensin receptor blocker (ARB), and captopril (Cp), an ACE inhibitor, from the 17th day of gestation (E17) to the 19th day of gestation (E19), in order to attenuate the activity of redundant RAS during the progressive stage of PAH, and evaluated its effect on physiological changes during pregnancy and tissue damages at E19.…”

Section: Introductionmentioning

confidence: 99%

Short-term suppression of the renin-angiotensin system in mice associated with hypertension during pregnancy

et al. 2012

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Abstract. Pregnancy-induced hypertension or pre-eclampsia is a major disorder that may result in serious complications for the mother and fetus. It is characterized from maternal hypertension in late pregnancy and peripheral tissue damage, including kidney, heart and placenta, and the fetus suffers from intrauterine growth retardation (IUGR) and high perinatal mortality. Recently, it has been postulated that angiotensin II (Ang II), a potent vasoconstrictor in the renin-angiotensin system (RAS), plays a pivotal role in the pathogenesis of pre-eclampsia; however, the beneficial effect of the suppression of RAS has not yet been fully elucidated. Previously, we generated a transgenic mouse model that developed pregnancyassociated hypertension (PAH) by the overproduction of Ang II in maternal circulation during late pregnancy. In addition, mice with PAH exhibited maternal and fetal abnormalities, such as proteinuria, cardiac hypertrophy, placental morphological changes and IUGR. In this study, in order to attenuate the activity of redundant RAS during the advanced stages of PAH, we administered olmesartan (Olm), an angiotensin receptor blocker, and captopril (Cp), an angiotensin converting enzyme inhibitor, from E17 to E19 days of gestation, and evaluated its effect on cardiac and placental abnormalities and fetal growth. Olm and Cp administration significantly lowered the blood pressure of mice with PAH, and placental histological change and severe IUGR were markedly ameliorated in both groups. On the contrary, Olm or Cp treatment had little effect on cardiac remodeling during the advanced stages of PAH. These findings highlight a variety of therapeutic actions of RAS repression on the progressive pathology of PAH in mice.

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“…2004; Sakairi et al. 2008; Ishimaru et al. 2012), SBP of PAH mice started to increase at day 13 of pregnancy (P13) and was significantly higher than that of WT mice during late pregnancy (Fig.…”

Section: Resultsmentioning

confidence: 99%

Angiotensin II accelerates mammary gland development independently of high blood pressure in pregnancy-associated hypertensive mice

et al. 2015

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Angiotensin II (AngII) is a vasopressor hormone that has critical roles in maintenance of normal blood pressure and pathogenesis of cardiovascular diseases. We previously generated pregnancy-associated hypertensive (PAH) mice by mating female human angiotensinogen transgenic mice with male human renin transgenic mice. PAH mice exhibit hypertension in late pregnancy by overproducing AngII. A recent study demonstrated that angiotensin II type I (AT1) receptor is expressed in mammary epithelial cells and its signaling is critical for mammary gland involution after weaning. However, the role of AngII-AT1 receptor signaling in the development of mammary gland during pregnancy remains unclear. In this study, to investigate the role of AngII-AT1 receptor signaling in mammary gland development during pregnancy, we analyzed the mammary gland of PAH mice. Histological and gene expression analyses revealed that lobuloalveolar development was accelerated with increased milk protein production and lipid accumulation in the mammary gland of PAH mice. Furthermore, AT1 receptor blocker treatment suppressed acceleration of mammary gland development in PAH mice, while the treatment of hydralazine, another antihypertensive drug, did not. These data suggest that AngII-AT1 receptor-induced signaling accelerates mammary gland development during pregnancy through hypertension-independent mechanism.

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Angiotensin Type 1 Receptor Blockade Prevents Cardiac Remodeling in Mice with Pregnancy-Associated Hypertension

Abstract: Pregnancy-induced hypertension (PIH) is a life-threatening disorder for both mother and fetus; cardiac dys

Cited by 14 publications

References 56 publications

Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

Short-term suppression of the renin-angiotensin system in mice associated with hypertension during pregnancy

Angiotensin II accelerates mammary gland development independently of high blood pressure in pregnancy-associated hypertensive mice

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