Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction

Ichihara, Sahoko; Senbonmatsu, Takaaki; Price, Edward; Ichiki, Toshihiro; Gaffney, F. Andrew; Inagami, Tadashi

doi:10.1161/01.cir.0000033826.52681.37

Cited by 88 publications

(83 citation statements)

References 39 publications

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“…Previous basic studies suggested that inhibition of plasminogen activators, MMPs, 9 or cardiac overexpression of FrzA can prevent cardiac rupture, 10 whereas deletion of angiotensin AT 2 receptor can aggravate it. 11 However, the upstream regulators of the genes that trigger these responses have not been studied. TNF-␣ is a master cytokine that is produced in significant quantities within the infarcted myocardium very soon after MI.…”

Section: Discussionmentioning

confidence: 99%

Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction

et al. 2004

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Background-We investigated the potential contributions of tumor necrosis factor-␣ (TNF-␣) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF Ϫ/Ϫ ) mice compared with C57/BL wild-type (WT) mice. Methods and Results-Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (nϭ120) of WT mice died of cardiac rupture, in contrast to 2.5% (nϭ80) of TNF Ϫ/Ϫ mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF Ϫ/Ϫ mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF Ϫ/Ϫ mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and ϮdP/dt max (68.3%/65.3%) in WT mice but a less significant decrease in ϮdP/dt max (25.8%/28.8%) in TNF Ϫ/Ϫ mice; (5) cardiac collagen volume fraction was lower in WT than in TNF Ϫ/Ϫ mice on days 3 and 7 but higher on day 28 compared with TNF Ϫ/Ϫ mice; and (6) a reduction in myocyte apoptosis in TNF Ϫ/Ϫ mice occurred on day 28 compared with WT mice. Conclusions-Elevated local TNF-␣ in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction

et al. 2004

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“…24,25,30,33,34 Fifth, although a 2-to 3-fold increase in myocardial collagen above the normal level results in increased LV stiffness and mild dysfunction, 35 a very small decrease in collagen below normal can lead to drastic consequences, 36,37 including LV dilation 4,22,34 and rupture. 33,38 In reperfused MI, decreased or damaged ECCM in the IZ 5,12,39 is associated with cardiac rupture. 5,39 Key Points to Remember About Pathobiology of Cardiac ECCM First, nearly 75% of the cells in the healthy heart are nonmyocytes, which include fibroblasts 18,21 that account for 90% to 95% of nonmyocyte cell mass 17,20,21 (Table 1).…”

Section: Ventricular Remodeling After MI and The Role Of Eccmmentioning

confidence: 99%

“…AngII type 2 (AT 2 ) receptors, which are re-expressed after MI and upregulated in heart failure, are more abundant in human than in rat hearts, are expressed in fibroblastlike cells, and mediate fibrosis, 7,49 and AT 2 loss prevents collagen deposition and causes cardiac rupture. 38 …”

Section: Jugdutt Ventricular Remodeling Postinfarction and The Eccmmentioning

confidence: 99%

Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix

2003

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L eft ventricular (LV) remodeling after myocardial infarction (MI) contributes significantly to LV dilation and dysfunction, and disability and death. Two paradigms, pertinent to antiremodeling therapy after MI (Figure 1), have evolved over the last 3 decades. Paradigm 1, LV remodeling is a major mechanism for disability and death, 1,2 has received a great deal of attention. In contrast, paradigm 2, remodeling of the extracellular collagen matrix (ECCM) plays a major role in LV remodeling, [3][4][5][6][7] whereby decrease, disruption, and/or defective composition of the ECCM promote LV dilation and rupture, 4 -7 has received little attention. A host of clinical trials showed that angiotensin-converting enzyme (ACE) inhibitors (ACE-Is) with or without aldosterone antagonists, angiotensin II (AngII) type 1 (AT 1 ) receptor blockers (ARBs), ␤-adrenergic blockers or reperfusion improve outcome in survivors of MI. 8 -10 Concurrent evidence has underscored the importance of preserving the ECCM during healing after MI. [2][3][4][5][6][7] However, the antifibrotic action of ACE-Is, aldosterone antagonists and ARBs on ECCM in the infarct zone (IZ) and noninfarct zone (NIZ), 6,7,9,11 and the reperfusion-induced damage to the ECCM in the IZ, 5,7,12 remain unreconciled with the benefits. 8 -10,13 Nevertheless, excessive ECCM, as in dilated ischemic cardiomyopathy after remote MI, 14,15 can contribute to LV diastolic dysfunction and poor outcome, 6 suggesting that antifibrotic drugs that target excess ECCM might be a logical therapeutic approach. This review focuses on the role of the ECCM in the evolution of LV remodeling after MI and the potential impact of therapies that target the ECCM. Ventricular Remodeling After MI and the Role of ECCMFive points merit emphasis. First, the LV remodeling process after MI is complex, dynamic, and time dependent, and progresses in parallel with healing over months. 1,2,7,16 Notably, it involves differential changes between the IZ and NIZ with respect to the following: (1) LV structure, shape, and topography 1,2 ( Figure 1); (2) cell type, such as myocytes and nonmyocytes (Table 1) 6,7,[17][18][19][20][21][22][23] ; (3) proteins, cytokines, and growth factors 7,24,25 ; and (4) the ECCM. 5-7,13-17,19 -23 Differential regional remodeling of the ECCM contributes significantly to global LV structural remodeling after MI (Figure 2) 7,9,26 and plays a pivotal role in paradigm 1. 3,6,7 Second, the post-MI heart shows remarkable capacity to adapt to the rather sudden development of an IZ and a NIZ. Thus, MI results in time-dependent damage to myocytes, nonmyocytes, and the ECCM in the IZ; ventricular dysfunction followed by volume overload and progressive dilation; reactive hypertrophy with interstitial fibrosis and increased collagen in the NIZ; gradual reparative fibrosis in the IZ 27 ; and vascular remodeling in the IZ and NIZ. 7 Third, several endogenous molecules that affect collagen synthesis and are upregulated after MI, and several agents that are used therapeutically for MI, affect co...

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“…Rupture is often associated with a transmural infarction, no prior history of angina pectoris, and a relatively large Q-wave infarct, and patients are predisposed to cardiac rupture by systemic and local factors such as hypertension, undue physical activity, diabetes, cardiac hypertrophy, and infarct expansion (1). Although the relevance of these risk factors remains undetermined, accumulated lines of evidence have suggested that disruption of ECM structures such as the collagen network in the infarcted myocardium leads to cardiac rupture (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

Matsumura¹,

Iwanaga²,

Mochizuki³

et al. 2005

J. Clin. Invest.

291

157

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MMPs are implicated in LV remodeling after acute myocardial infarction (MI).To analyze the role of MMP-2, we generated MI by ligating the left coronary artery of MMP-2-KO and WT mice, the latter of which were administered orally an MMP-2-selective inhibitor or vehicle (TISAM). The survival rate was significantly higher in MMP-2-KO and TISAM-treated mice than in control WT mice. The main cause of mortality in control WT mice was cardiac rupture, which was not observed in MMP-2-KO or TISAM-treated mice. Control WT mice, but not MMP-2-KO or TISAM-treated mice, showed activation of the zymogen of MMP-2, strong gelatinolytic activity, and degradation of ECM components, including laminin and fibronectin, in the infarcted myocardium. Although infarcted cardiomyocytes in control WT mice were rapidly removed by macrophages, the removal was suppressed in MMP-2-KO and TISAM-treated mice. Macrophage migration was induced by the infarcted myocardial tissue from control WT mice and was inhibited by treatment of macrophages with laminin or fibronectin peptides prior to migration assay. These data suggest that inhibition of MMP-2 activity improves the survival rate after acute MI by preventing cardiac rupture and delays post-MI remodeling through a reduction in macrophage infiltration.

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Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction

Cited by 88 publications

References 39 publications

Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction

Excessive Tumor Necrosis Factor Activation After Infarction Contributes to Susceptibility of Myocardial Rupture and Left Ventricular Dysfunction

Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix

Targeted deletion or pharmacological inhibition of MMP-2 prevents cardiac rupture after myocardial infarction in mice

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