Cardiac hypertrophy is enhanced in PPAR -/- mice in response to chronic pressure overload

Smeets, Pascal J H; Teunissen, Birgit E.J.; Willemsen, P. H. M.; Nieuwenhoven, Frans A. van; Brouns, A.; Janssen, Ben J. A.; Cleutjens, Jack P.M.; Staels, Bart; Vusse, Ger J.; Bilsen, Marc van

doi:10.1093/cvr/cvn001

Cited by 117 publications

(100 citation statements)

References 40 publications

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“…In addition, activation of inflammatory signaling pathways has been considered to promote both cardiac hypertrophy and fibrosis, and inhibition of inflammation may attenuate the development of cardiac hypertrophy [34]. In our study, we found that mRNA levels of TNF-α and IL-6 increased in cellular (ET-1) and animal (AAC) models of cardiac hypertrophy, but PMQ treatment could significantly prevent its incremental trend and alleviate progression to cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 52%

“…It has been reported that PPAR α, in addition to its well-documented role in cardiac lipid metabolism, modulates immune-inflammatory signaling pathways and the expression of extracellular matrix genes in normal cardiac muscle [36]. Some studies also show that the absence of PPAR α results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodeling [34,37]. These findings indicate that PPAR α exerts salutary effects during cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

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In Vivo and In Vitro Protective Effects of Pentamethylquercetin on Cardiac Hypertrophy

Chen

et al. 2011

Cardiovasc Drugs Ther

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

In Vivo and In Vitro Protective Effects of Pentamethylquercetin on Cardiac Hypertrophy

Chen

et al. 2011

Cardiovasc Drugs Ther

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“…Further studies demonstrated that the absence of PPARa results in a more pronounced hypertrophic growth response and signs of functional deterioration (28). A similar relationship between PPARa deficiency and increased oxidative stress was also found in an alcoholic liver disease model (24).…”

Section: Discussionmentioning

confidence: 66%

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

et al. 2010

Antioxidants & Redox Signaling

195

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Mitochondria are a principal site for generation of reactive oxygen species (ROS) in the heart. Peroxisome proliferator activated receptor g coactivator 1a (PGC-1a) plays an important role in regulating mitochondrial biogenesis and myocardial metabolism, but whether PGC-1a can simultaneously upregulate myocardial mitochondrial antioxidants has not been studied. In the present study, we examined the effect of PGC-1a deficiency (PGC-1a -=-) on oxidative stress and expression of a group of mitochondrial antioxidants in normal hearts and in hearts exposed to chronic systolic pressure overload produced by transverse aortic constriction (TAC). We found that PGC-1a -=-caused moderate but significant decreases of myocardial mitochondrial antioxidant enzymes such as SOD2, and thioredoxin (Trx2), but had no effect on expression of myocardial oxidative stress markers and left ventricular (LV) function under basal conditions. However, in response to TAC for 6 weeks, PGC-1a -=-mice showed greater increases of myocardial oxidative stress markers 3'-nitrotyrosine and 4-hydroxynonenal, more severe LV hypertrophy and dilatation, pulmonary congestion, and a greater reduction of LV fractional shortening and dP=dt max than did wild-type hearts. SOD mimetic MnTMPyP treatment (6 mg=kg=day) significantly attenuated TAC-induced LV hypertrophy and dysfunction in PGC-1a -=-mice. These data indicate that PGC-1a plays an important role in regulating expression of myocardial mitochondrial antioxidants SOD2 and Trx2 and in protecting hearts against TAC-induced myocardial oxidative stress, hypertrophy, and dysfunction. Antioxid.

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“…PPAR alpha, the predominant PPAR isoform in the heart, has been implicated in hypertrophic signaling. Smeets et al [14] showed that the absence of PPAR alpha results in a more pronounced hypertrophic growth response and cardiac dysfunction, which are associated with the increased expression of inflammatory markers and extracellular matrix remodeling. PPAR gamma has been shown [15] to attenuate angiotensin-II-induced hypertrophic gene expression and increase cardiomyocyte size in vitro.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

Qin

et al. 2010

Acta Pharmacol Sin

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Aim:The examine the cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice (ApoE-/-mice) fed a "Western-style diet" and the effect of simvastatin intervention. Methods: Male ApoE-/-mice (n=36) were fed a "Western-style diet" from the age of 8 weeks. After 16 weeks, they were randomly given either simvastatin (25 mg·kg -1 ·d -1 ) or normal saline (control group) by gavage for 8, 16, or 24 weeks. The left ventricular (LV) wall thickness and diameter of the myocardial cells were determined with Hematoxylin-Eosin stain, and the level of fibrosis of the myocardial matrix was assessed with Masson stain. Real-time quantitative polymerase chain reaction and Western blotting analysis were used to determine the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9), Cathepsin S (Cat S), and the peroxisome proliferator-activated receptors (PPARs) in the myocardium of ApoE-/-mice. Results: ApoE-/-mice fed a "Western-style diet" showed an significant age-dependent increase in total cholesterol (TC), LV wall thickness, myocardial cell diameter and LV collagen content (P<0.05). The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05). Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05) . Conclusion: ApoE-/-mice fed a "Western-style diet" had cardiac hypertrophy and fibrosis, which worsened with age. Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S.

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Cardiac hypertrophy is enhanced in PPAR -/- mice in response to chronic pressure overload

Cited by 117 publications

References 40 publications

In Vivo and In Vitro Protective Effects of Pentamethylquercetin on Cardiac Hypertrophy

In Vivo and In Vitro Protective Effects of Pentamethylquercetin on Cardiac Hypertrophy

PGC-1α Regulates Expression of Myocardial Mitochondrial Antioxidants and Myocardial Oxidative Stress After Chronic Systolic Overload

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

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