Peroxisome Proliferator Activated Receptor (PPAR)α Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes

Liang, Faquan; Wang, Feng; Gardner, David G.

doi:10.1210/en.2002-0217

Cited by 76 publications

(64 citation statements)

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“…Expression of PPARG (peroxisome proliferator-activated receptor ␥), its heterodimeric partner RXRG (retinoid X receptor ␥), and coactivator PPARGC1A were all decreased in K-line hearts (Supplemental Table S3). Furthermore, the target genes of PPARG (11,36,46,56), e.g., SPP1, NPPB (natriuretic peptide precursor B), VCAM1, and TPM2 (tropomyosin 2␤), were also significantly altered (Supplemental Table S3) in K-line mice. These data indicate that PPARG pathway may contribute to cardiac pathology in K-line mice.…”

Section: Resultsmentioning

confidence: 99%

Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Xue¹,

Mraiche

Zhou³

et al. 2010

Physiological Genomics

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In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

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Section: Resultsmentioning

confidence: 99%

Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Xue¹,

Mraiche

Zhou³

et al. 2010

Physiological Genomics

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“…We have previously reported that a number of nuclear receptor agonists including the peroxisome proliferator activator receptors (PPAR), subtypes ␣ and ␥, vitamin D receptor, and retinoic acid/retinoid receptors attenuate ET-1-dependent hypertrophy and hBNP promoter activity in neonatal cardiac myocytes (51,52). Moreover, pioglitazone, a PPAR␥ agonist, has been shown to abrogate left ventricular remodeling and myocyte hypertrophy following experimental myocardial infarction (53).…”

Section: Discussionmentioning

confidence: 99%

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Anderson¹,

Wang²,

Gardner

2004

Journal of Biological Chemistry

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The epidermal growth factor receptor (EGFR) and ectoshedding of heparin-binding epidermal growth factor (HBEGF), an EGFR ligand, have been linked to the development of cardiac myocyte hypertrophy. However, the precise role that the liganded EGFR plays in the transcriptional activation of the gene program that accompanies hypertrophy remains undefined. Utilizing the human (h) BNP gene as a model of hypertrophy-dependent gene activation, we show that activation of the EGFR plays an important role in mediating mechanical strain-dependent stimulation of the hBNP promoter. Strain promotes endothelin (ET) generation through NAD(P)H oxidase-dependent production of reactive oxygen species. ET in turn induces metalloproteinase-mediated cleavage of pro-HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity. HBEGF also stimulates other phenotypic markers of hypertrophy including protein synthesis and sarcomeric assembly. The antioxidant N-acetylcysteine or the NAD(P)H oxidase inhibitor, apocynin, inhibited strain-dependent activation of the ET-1 promoter, HBEGF shedding, and hBNP promoter activation. The metalloproteinase inhibitor, GM-6001, prevented the induction of HBEGF ectoshedding and the hBNP promoter response to strain, suggesting a critical role for the metalloproteinase-dependent cleavage event in signaling the strain response. These findings suggest that metalloproteinase activity as an essential step in this pathway may prove to be a relevant therapeutic target in the management of cardiac hypertrophy.

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“…The PPAR␣ ligands, fenofibrate and Wy14,463, inhibited cardiac myocyte hypertrophy in response to endothelin. 118 Human genetic studies identified a significant association between a PPAR␣ gene polymorphism and development of physiological or pathological left ventricular hypertrophy though did not establish that the anti-hypertrophic effects of PPAR␣ were linked to metabolic changes. 119 Similar antihypertrophic action has been observed for other NR ligands, including 1,25 dihydroxyvitamin D and retinoic acid, which act through vitamin D receptor (VDR)/RXR heterodimers.…”

Section: Huss and Kelly Nuclear Receptor And Cardiac Energetics 573mentioning

confidence: 99%

Nuclear Receptor Signaling and Cardiac Energetics

Huss

Kelly

2004

Circulation Research

409

322

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Abstract-The heart has a tremendous capacity for ATP generation, allowing it to function as an efficient pump throughout the life of the organism. The adult myocardium uses either fatty acid or glucose oxidation as its main energy source. Under normal conditions, the adult heart derives most of its energy through oxidation of fatty acids in mitochondria. However, the myocardium has a remarkable ability to switch between carbohydrate and fat fuel sources so that ATP production is maintained at a constant rate in diverse physiological and dietary conditions. This fuel selection flexibility is important for normal cardiac function. Although cardiac energy conversion capacity and metabolic flux is modulated at many levels, an important mechanism of regulation occurs at the level of gene expression. The expression of genes involved in multiple energy transduction pathways is dynamically regulated in response to developmental, physiological, and pathophysiological cues. This review is focused on gene transcription pathways involved in short-and long-term regulation of myocardial energy metabolism. Much of our knowledge about cardiac metabolic regulation comes from studies focused on mitochondrial fatty acid oxidation. The genes involved in this key energy metabolic pathway are transcriptionally regulated by members of the nuclear receptor superfamily, specifically the fatty acid-activated peroxisome proliferator-activated receptors (PPARs) and the nuclear receptor coactivator, PPAR␥ coactivator-1␣ (PGC-1␣). The dynamic regulation of the cardiac PPAR/PGC-1 complex in accordance with physiological and pathophysiological states will be described. (Circ Res. 2004;95:568-578.)

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Peroxisome Proliferator Activated Receptor (PPAR)α Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes

Cited by 76 publications

References 45 publications

Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Nuclear Receptor Signaling and Cardiac Energetics

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Peroxisome Proliferator Activated Receptor (PPAR)α Agonists Inhibit Hypertrophy of Neonatal Rat Cardiac Myocytes

Cited by 76 publications

References 45 publications

Elevated myocardial Na+/H+exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Elevated myocardial Na+/H+exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene

Nuclear Receptor Signaling and Cardiac Energetics

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Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

Elevated myocardial Na⁺/H⁺exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy