Targeted deletion of MMP-2 attenuates early LV rupture and late  remodeling after experimental myocardial infarction

Hayashidani, Shunji; Tsutsui, Hiroyuki; Ikeuchi, Masaki; Shiomi, Tetsuya; Matsusaka, Hidenori; Kubota, Takeshi; Imanaka‐Yoshida, Kyoko; Itoh, Takeshi; Takeshita, Akira

doi:10.1152/ajpheart.00207.2003

Cited by 281 publications

(248 citation statements)

References 28 publications

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“…[30][31][32] Recent studies using MMP knockout mice or administration of MMP inhibitors have provided insights into the involvement of particular MMP species in unfavorable LV remodeling after MI. [33][34][35][36] In this study, the area of myocardial fibrosis, TGF-b1 protein level, CTGF and OPN mRNA levels, and the activity of MMP-2 and MMP-9 were all increased in the noninfarcted myocardium 7 days after induction of MI compared with sham-operated rats. Importantly, Telmisartan ameliorated these unfavorable changes.…”

Section: Discussionmentioning

confidence: 47%

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) leads to cardiac dysfunction. We examined whether Telmisartan, an angiotensin (Ang) II type I receptor blocker (ARB), could improve the recovery of LV function in a rat model of MI. The effect of Telmisartan as a peroxisome proliferator-activated receptor-g (PPAR-g) agonist was also investigated. After 28 days of MI, a significant improvement of survival was observed in the Telmisartan-treated rat group compared with the vehicle control rat group, non-PPAR-g agonistic ARB (Losartan)-treated rat group, and Telmisartan plus specific PPAR-g antagonist (GW9662)-treated rat group. Although no significant differences of blood pressure or infarct size were observed among these four groups, the Telmisartan group had better systolic and diastolic LV function. There was a significant reduction of the plasma brain natriuretic peptide level, cardiac fibrosis area, infiltration of macrophages, size of cardiomyocytes, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive myocytes, activation of matrix metalloproteinases-2 and -9 (MMPs-2/9), and expression of transforming growth factor b-1 (TGF-b1), connective tissue growth factor (CTGF), and osteopontin (OPN), while expression of PPAR-g and activation of tissue inhibitor of metalloproteinase-1 (TIMP-1) was enhanced, in the noninfarcted myocardium of rats from the Telmisartan group compared with the other three groups. To mimic ischemic conditions in vitro, neonatal rat cardiomyocytes and cardiac fibroblasts were incubated in hypoxic condition for 24 h. Increased transcriptional activation of PPAR-g and TIMP-1, and inhibition of TGF-b1 expression were observed in cardiomyocytes, while decreased activation of MMPs-2/9 and decrease in CTGF and OPN expression was seen in cardiac fibroblasts cultured with Telmisartan. In conclusion, Telmisartan prevented unfavorable cardiac remodeling through a reduction of cardiac hypertrophy and fibrosis. An anti-inflammatory effect and PPAR-g activation were suggested to be important in addition to suppression of Ang II activity. Unfavorable left ventricular (LV) remodeling after myocardial infarction (MI) is characterized by hypertrophy associated with interstitial fibrosis of the noninfarcted myocardium, and causes LV dilatation and cardiac dysfunction. It is known that angiotensin II (Ang II) has a crucial role in the development of unfavorable LV remodeling, and recent studies based on animal experiments have demonstrated that treatment with an Ang-converting enzyme inhibitor (ACE-I) and/or Ang II type I receptor blocker (ARB) can attenuate unfavorable LV remodeling. 1,2 Moreover, other experimental studies suggested that activation of peroxisome proliferator-activated receptor-g (PPAR-g), a transcription factor, improves unfavorable LV remodeling after MI. [3][4][5] PPAR-g agonists not only regulate insulin sensitivity, but also have an anti-inflammatory effect by inhibiting the expression of adhesion molecules, cytokines, and chemokines, as well ...

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Section: Discussionmentioning

confidence: 47%

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Maejima

Okada

Haraguchi

et al. 2011

Laboratory Investigation

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“…In this study, we showed increased induction of gelatinase activity (i.e., of MMP-9 and MMP-2) in the noninfarcted myocardium 7 days after induction of MI. Recent studies using transgenic mouse models of MMP deletion and MMP inhibitor have provided further insight into the involvement of particular MMP species in LV remodeling after MI (5,11,25). These data suggest the importance of gelatinases in the development of LV remodeling.…”

Section: Diastolic Dysfunction and Nf-b Inhibitionmentioning

confidence: 92%

Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

Onai¹,

Suzuki²,

Maejima³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

107

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August 18, 2006; doi:10.1152/ajpheart.00549.2006.-Several studies have demonstrated that NF-B is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-B is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of I B that acts via inhibition of IKK-␤, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P Ͻ 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV enddiastolic area: vehicle, 74.13 Ϯ 3.57 mm 2 ; IMD-0354, 55.00 Ϯ 3.73 mm 2 ; P Ͻ 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 Ϯ 0.26; IMD-0354, 2.61 Ϯ 0.24; P Ͻ 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 Ϯ 14.87 pg/ml; IMD-0354, 110.75 Ϯ 6.41 pg/ml; P Ͻ 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-␤1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-B activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI. experimental heart failure; nuclear factor-b; matrix metalloproteinase; echocardiography MYOCARDIAL INFARCTION (MI) frequently leads to left ventricular (LV) dilatation and associated interstitial fibrosis in the noninfarcted myocardium. This adverse LV remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after MI (20). One of the recent conceptual advances in our understanding of the pathogenesis of LV remodeling is that this process is driven by the overexpression of various factors, including proinflammatory cytokines, angiotensin II, and norepinephrine, which have direct pathophysiological effects on cardiac myocytes, noncardiac myocytes, and the extracellular matrix (20). Although the expression of proinflammatory cytokines may be involved in wound healing after MI, it is believed that the overexpression of cytokines damages cardiac tissue and evokes excess deposition of fibrotic components, even in the noninfarcted myocardium.Several recent studies reported that nuclear factor-B (NF-B) is involved in the pathogenesis of heart failure (7, 35). Activation of NF-B induces activation of genetic programs that lead to transactivation of cytokines, chemokines, and matrix metalloproteinases (MMPs), promoting inflammatory and fibrotic responses that participate in the progre...

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“…Following myocardial infarction, catastrophic mechanical complications, such as cardiac rupture (129), are associated with accentuated matrix degradation or perturbed deposition of new structural matrix (130). These can be treated through application of a patch containing ECM proteins to restore the structural integrity of the ventricle (131).…”

Section: Therapeutic Ecm Targeting In Injured and Remodeling Myocardiummentioning

confidence: 99%

The extracellular matrix in myocardial injury, repair, and remodeling

Frangogiannis¹

2017

Journal of Clinical Investigation

371

296

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Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction

Cited by 281 publications

References 28 publications

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Telmisartan, a unique ARB, improves left ventricular remodeling of infarcted heart by activating PPAR gamma

Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction

The extracellular matrix in myocardial injury, repair, and remodeling

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