Angiotensin II Type 1A Receptor Knockout Mice Display Less Left Ventricular Remodeling and Improved Survival After Myocardial Infarction

Harada, Koichiro; Sugaya, Takeshi; Murakami, Kazuo; Yazaki, Yoshio; Komuro, Issei

doi:10.1161/01.cir.100.20.2093

Cited by 190 publications

(151 citation statements)

References 37 publications

(40 reference statements)

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“…On the other hand, late remodeling progresses 1 to 2 months after MI, involving LV dilation, myocyte hypertrophy, and interstitial fibrosis. 3,21,22 In the present study, an interstitial fibrosis, which characterizes the late remodeling, was not evident either in Agtr2ϩ or Agtr2-mice, supporting that the process of the late LV remodeling had not started in these mice. In fact, the interstitial fibrosis developed in the 4th week after MI, the extent of which was significantly larger in Agtr2-mice than in Agtr2ϩ mice (data not shown).…”

Section: Discussionsupporting

confidence: 62%

“…6 It has been suggested that AT1R signaling mediates vasoconstriction, aldosterone secretion, cardiomyocyte hypertrophy, proliferation of fibroblasts, interstitial collagen deposition, and catecholamine release, all of which are implicated in progression of LV remodeling. 7,8 Harada et al 3 recently reported that AT1R gene-knockout mice had less LV remodeling and improved survival after MI. A deletion of AT1R or a blockade of AT1R with specific antagonists may result in selective binding of Ang II to the AT2R, indicating that the effect of AT1R blockade could be in part mediated by the effect of AT2R.…”

mentioning

confidence: 99%

“…1,2 A substantial body of evidence 1,[3][4][5] has suggested that angiotensin II (Ang II) plays a critical role in the development of post-MI LV remodeling. Ang II has 2 major receptor subtypes, AT1 receptor (AT1R) and AT2R, both of which are expressed in the heart.…”

mentioning

confidence: 99%

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Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling

et al. 2003

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Abstract-The aim of this study was to determine the role of the AT2 receptor (AT2R) in left ventricular (LV) remodeling after myocardial infarction (MI). The left anterior descending arteries were ligated in AT2R gene knockout (Agtr2-) and wild-type (Agtr2ϩ) mice. The LV remodeling was evaluated by echocardiography and histology over a period of 2 weeks after MI. The infarct sizes in hearts excised from Agtr2ϩ and Agtr2-mice on day 1 were similar. The mortality rate of Agtr2-mice (62.9%) on day 14 after MI was significantly (PϽ0.05) higher than that of Agtr2ϩ mice (39.7%). Accordingly, LV/body weight ratios (3.7Ϯ0.2 versus 3.0Ϯ0.1 on day 14) and LV end-diastolic (4.8Ϯ0.3 versus 3.9Ϯ0.4 mm on day 7) and end-systolic (4.4Ϯ0.3 versus 3.2Ϯ0.6 mm on day 7) dimensions evaluated by echocardiography were significantly greater in Agtr2-than in Agtr2ϩ mice. The rates of ventricular arrhythmia, rates of cardiac rupture, and blood pressures in the 2 strains were similar after MI. Myocyte cross-sectional areas were increased after MI, but the magnitudes were similar in Agtr2ϩ and Agtr2-mice, indicating the greater increases in LV dimensions and weight in Agtr2-mice are due to elongation of myocyte length and/or an increase in the interstitial weight (including vasculatures, infiltrated cells, and interstitial fluid). Interstitial fibrosis in remote myocardium was not evident in either strain. These results indicate AT2R plays a significant role in the protection against early development of LV dilation, thereby reducing the early mortality rate after MI. Key Words: mice Ⅲ myocardial infarction Ⅲ receptors, angiotensin Ⅲ remodeling M yocardial infarction induces global changes in ventricular architecture, called post-myocardial infarction (MI) left ventricular (LV) remodeling, which involves LV dilation, myocyte hypertrophy, and interstitial fibrosis, leading to a deterioration in LV function that is associated with increased rate of mortality. 1,2 A substantial body of evidence 1,3-5 has suggested that angiotensin II (Ang II) plays a critical role in the development of post-MI LV remodeling. Ang II has 2 major receptor subtypes, AT1 receptor (AT1R) and AT2R, both of which are expressed in the heart. 6 It has been suggested that AT1R signaling mediates vasoconstriction, aldosterone secretion, cardiomyocyte hypertrophy, proliferation of fibroblasts, interstitial collagen deposition, and catecholamine release, all of which are implicated in progression of LV remodeling. 7,8 Harada et al 3 recently reported that AT1R gene-knockout mice had less LV remodeling and improved survival after MI. A deletion of AT1R or a blockade of AT1R with specific antagonists may result in selective binding of Ang II to the AT2R, indicating that the effect of AT1R blockade could be in part mediated by the effect of AT2R. 7 However, little is known about the role played by AT2R in post-MI LV remodeling. The AT2R is thought to have opposite effect to AT1R and has been shown to suppress myocardial hypertrophy, 9 -11 fibroblast proliferation, 10,12 and ...

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Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 99%

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Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling

et al. 2003

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“…G q activity has been inhibited in transgenic mice by overexpression of the carboxyl-terminal peptide of G ␣q ; inhibitor-expressing transgenic mice have a reduced hypertrophic response to aortic constriction (12), demonstrating that G q activation is necessary for this hypertrophic response. Overexpression and knockout of the AT 1 receptor produce phenotypes that are consistent with the G q data (13,14 (18). These data raise some interesting questions.…”

supporting

confidence: 71%

A positive feedback loop contributes to the deleterious effects of angiotensin

Brunton

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…17,18 Our data suggest that iron deposition may exacerbate the cardiac fibrosis induced by angiotensin II. The findings that the myocardial fibrosis that occurs after myocardial ischemia can be attenuated by angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist 19 and that less cardiac fibrosis is observed in the AT 1 receptor knockout mouse than in wild-type 20 suggest that angiotensin II has a crucial role in the development of cardiac fibrosis. Several factors that possibly mediate the fibrogenic effects of angiotensin II have been reported, such as transforming growth factor-␤ and cardiac aldosterone.…”

Section: Discussionmentioning

confidence: 99%

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

et al. 2002

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Background-Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results-Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions-Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II.In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

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Angiotensin II Type 1A Receptor Knockout Mice Display Less Left Ventricular Remodeling and Improved Survival After Myocardial Infarction

Abstract: These results indicate that AT(1A) signals play a pivotal role in the progression of LV remodeling after MI, resulting in overt heart failure.

Cited by 190 publications

References 37 publications

Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling

Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling

A positive feedback loop contributes to the deleterious effects of angiotensin

Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

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