Pioglitazone, a Peroxisome Proliferator–Activated Receptor-γ Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

Shiomi, Tetsuya; Tsutsui, Hiroyuki; Hayashidani, Shunji; Suematsu, Nobuhiro; Ikeuchi, Masaki; Wen, Jing; Ishibashi, Masayoshi; Kubota, Takeshi; Egashira, Kensuke; Takeshita, Akira

doi:10.1161/01.cir.0000039346.31538.2c

Cited by 250 publications

(177 citation statements)

References 39 publications

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“…41 In addition to these vasculoprotective effects, PPAR␥ activators exert a positive effect on the myocardium by limiting left ventricular remodeling and failure after a myocardial infarction. 42 The results of the present study suggest that part of the beneficial cardiovascular effects observed after treatment with glitazones may be due to the favorable effect these PPAR␥ agonists have on EPCs. A limitation to the present study is that the in vivo effects of CRP and rosiglitazone on EPC number and vasculogenic function were not determined; however, such studies are currently being conducted.…”

Section: Verma Et Al Crp and Epc Differentiation 2063mentioning

confidence: 59%

C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function

et al. 2004

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Background-Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown. Methods and Results-EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 g/mL), rosiglitazone (1 mol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations Ն15 g/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-␥ (PPAR␥) agonist. Conclusions-Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPAR␥ agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.

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Section: Verma Et Al Crp and Epc Differentiation 2063mentioning

confidence: 59%

C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function

et al. 2004

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“…28 Previous experimental investigations revealed that PPAR-g agonists can improve LV systolic and diastolic function by attenuating unfavorable LV remodeling in animal models of MI. [3][4][5] Telmisartan inhibits Ang II type I receptor (AT1R) not only by direct blockade of AT1R but also by downregulation of AT1R expression through a PPAR-g-mediated pathway, thereby inhibiting the RAAS more completely than other ARBs. 29 Thus, Telmisartan effectively inhibits unfavorable LV remodeling via both AT1R blockade and an anti-inflammatory effect mediated by PPAR-g activation.…”

Section: Discussionmentioning

confidence: 99%

“…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 as anti-fibrotic activity by inhibiting transforming growth factor b-1 (TGF-b1) signaling, and the activity of matrix metalloprotease (MMP)-2/9 and the osteopontin (OPN). [6][7][8][9] Telmisartan is a structurally unique ARB that acts as a partial PPAR-g agonist (activating the receptor 25-30% of the maximum level achieved by full PPAR-g agonists) as well as an ARB, 10 thereby improving insulin resistance and lipid metabolism as well as reducing the blood pressure.…”

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confidence: 99%

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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“…Myocardial infarct sizes were determined by planimetry in three cryosections stained with hematoxylin͞eosin and expressed as [%] of LV circumference (20).…”

Section: Methodsmentioning

confidence: 99%

Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

Heineke

Ruetten

Willenbockel

et al. 2005

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

142

138

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Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause for heart failure. Molecular modifiers of the remodeling process remain poorly defined. Patients with heart failure after MI have reduced LV expression levels of muscle LIM protein (MLP), a component of the sarcomeric Z-disk that is involved in the integration of stress signals in cardiomyocytes. By using heterozygous MLP mutant (MLP ؉/؊ ) mice, we explored the role of MLP in post-MI remodeling. LV dimensions and function were similar in sham-operated WT and MLP ؉/؊ mice. After MI, however, MLP ؉/؊ mice displayed more pronounced LV dilatation and systolic dysfunction and decreased survival compared with WT mice, indicating that reduced MLP levels predispose to adverse LV remodeling. LV dilatation in MLP ؉/؊ mice was associated with reduced thickening but enhanced elongation of cardiomyocytes. Activation of the stress-responsive, prohypertrophic calcineurinnuclear factor of activated T-cells (NFAT) signaling pathway was reduced in MLP ؉/؊ mice after MI, as shown by a blunted transcriptional activation of NFAT in cardiomyocytes isolated from MLP ؉/؊ ͞NFAT-luciferase reporter gene transgenic mice. Calcineurin was colocalized with MLP at the Z-disk in WT mice but was displaced from the Z-disk in MLP ؉/؊ mice, indicating that MLP is essential for calcineurin anchorage to the Z-disk. In vitro assays in cardiomyocytes with down-regulated MLP confirmed that MLP is required for stress-induced calcineurin-NFAT activation. Our study reveals a link between the stress sensor MLP and the calcineurin-NFAT pathway at the sarcomeric Z-disk in cardiomyocytes and indicates that reduced MLP-calcineurin signaling predisposes to adverse remodeling after MI.heart failure ͉ stress signaling C hronic heart failure is a worldwide epidemic. Recently, a fundamental shift in the underlying etiology of heart failure has occurred, in which the most common cause of heart failure is no longer hypertension or valvular disease, but myocardial infarction (MI) (1). MI induces profound alterations of left ventricular (LV) architecture with scar formation, ventricular dilatation, and hypertrophy of the noninfarcted (remote) myocardium (2). Biomechanical stress and humoral growth factors are important mediators of this remodeling process (3, 4). At the level of the single cardiomyocyte, post-MI LV remodeling is characterized by increases in cell diameter and cell length and alterations in gene expression levels (5-7).The Z-disk is a multiprotein complex located at the interface of the cytoskeleton, the contractile apparatus, and the sarcolemma in cardiomyocytes (8). Muscle LIM protein (MLP), which is tethered to the Z-disk via its interacting partners, ␣-actinin and telethonin, has been proposed to be an essential part of the mechanical stretch sensor machinery (9) and to be involved in the transmission of humoral growth signals in cardiomyocytes (10). Intriguingly, myocardial MLP levels are reduced by Ϸ50% in patients with heart failure after MI (11). However, ...

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Pioglitazone, a Peroxisome Proliferator–Activated Receptor-γ Agonist, Attenuates Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction

Cited by 250 publications

References 39 publications

C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function

C-Reactive Protein Attenuates Endothelial Progenitor Cell Survival, Differentiation, and Function

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

Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc

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