PPARs: Protectors or Opponents of Myocardial Function?

Pol, Christine J.; Lieu, Melissa; Drosatos, Konstantinos

doi:10.1155/2015/835985

Cited by 41 publications

(40 citation statements)

References 228 publications

(291 reference statements)

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“…TZDs have multiple effects on the cardiovascular system, which provides a potential explanation for the increased incidence of heart failure in TZD-treated patients (30). TZD treatment is associated with cardiac hypertrophy in rodents (31,32). In Rosi-treated WT mice, we did observe increased heart weight, and this effect was absent in 2KR mice ( Figure 7A and Supplemental Figure 12A).…”

Section: 0mentioning

confidence: 81%

PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects

Kraakman¹,

Liu²,

Postigo-Fernandez³

et al. 2018

Journal of Clinical Investigation

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Section: 0mentioning

confidence: 81%

PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects

Kraakman¹,

Liu²,

Postigo-Fernandez³

et al. 2018

Journal of Clinical Investigation

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“…57 Using a statistical analysis, we identified mRNA differences associated with sex and hypertrophy, and using STRING9, we built a gene interaction network to identify subnetworks that are likely to be involved in the difference in hypertrophy between males and females. As shown in Figure 7, PPARa, a well-established factor in hypertrophy, [37][38][39][40][41] is at the center of this hub. PPARa, a transcription factor that regulates metabolism, was previously reported to play a role in regulation of hypertrophy; however, it has not been implicated in sex differences in hypertrophy.…”

Section: Discussionmentioning

confidence: 93%

“…During hypertrophy, the heart's metabolism shifts with an increase in glycolysis and a decreased reliance on fatty acid oxidation, consistent with a reversion to a fetal gene program with hypertrophy. Because PPARα is known to regulate fatty acid oxidation, it is not surprising that PPARα has been well documented to play a role in cardiac hypertrophy, although there is some disagreement as to whether it is beneficial or detrimental . Most studies, but not all, report a decrease in PPARα with hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…PPARa has been shown previously to be involved in regulating hypertrophy. [37][38][39][40][41][42] Esrrg (estrogen-related receptor c), a regulator of mitochondrial function that has been shown to play a role in regulating hypertrophy, is also found in this subnetwork. Intriguingly, a number of genes involved in circadian rhythms were also shown to have a sex and disease interaction; these include Per1, Arntl (aryl hydrocarbon receptor nuclear translocator-like protein 1; also known as Bmal [brain and muscle ARNT]), and Ccrn4ls.…”

Section: Identification Of a Gene Subnetwork That Is The Most Relevanmentioning

confidence: 99%

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A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

Harrington

Fillmore

Gao

et al. 2017

JAHA

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BackgroundHeart failure preceded by hypertrophy is a leading cause of death, and sex differences in hypertrophy are well known, although the basis for these sex differences is poorly understood.Methods and ResultsThis study used a systems biology approach to investigate mechanisms underlying sex differences in cardiac hypertrophy. Male and female mice were treated for 2 and 3 weeks with angiotensin II to induce hypertrophy. Sex differences in cardiac hypertrophy were apparent after 3 weeks of treatment. RNA sequencing was performed on hearts, and sex differences in mRNA expression at baseline and following hypertrophy were observed, as well as within‐sex differences between baseline and hypertrophy. Sex differences in mRNA were substantial at baseline and reduced somewhat with hypertrophy, as the mRNA differences induced by hypertrophy tended to overwhelm the sex differences. We performed an integrative analysis to identify mRNA networks that were differentially regulated in the 2 sexes by hypertrophy and obtained a network centered on PPARα (peroxisome proliferator‐activated receptor α). Mouse experiments further showed that acute inhibition of PPARα blocked sex differences in the development of hypertrophy.ConclusionsThe data in this study suggest that PPARα is involved in the sex‐dimorphic regulation of cardiac hypertrophy.

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“…Cardiac-specific PPARβ/δ overexpressing transgenic mice do not display myocardial lipid accumulation or cardiac dysfunction, even on high fat diet [61]. Taken together, there is much controversy whether PPARs are friends or foes in lipid-induced cardiomyopathy [62].…”

Section: Peroxisome Proliferator-activated Receptors (Ppars)mentioning

confidence: 99%

Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

Liu

Neumann

Glatz

et al. 2018

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Long-chain fatty acids are the main cardiac substrates from which ATP is generated continually to serve the high energy demand and sustain the normal function of the heart. Under healthy conditions, fatty acid β-oxidation produces 50-70% of the energy demands with the remainder largely accounted for by glucose. Chronically increased dietary lipid supply often leads to excess lipid accumulation in the heart, which is linked to a variety of maladaptive phenomena, such as insulin resistance, cardiac hypertrophy and contractile dysfunction. CD36, the predominant cardiac fatty acid transporter, has a key role in setting the heart on a road to contractile dysfunction upon the onset of chronic lipid oversupply by translocating to the cell surface and opening the cellular 'doors' for fatty acids. The sequence of events after the CD36-mediated myocellular lipid accumulation is less understood, but in general it has been accepted that the excessively imported lipids cause insulin resistance, which in turn leads to contractile dysfunction. There are several gaps of knowledge in this proposed order of events which this review aims to discuss. First, the molecular mechanisms underlying lipid-induced insulin resistance are not yet completely disclosed. Specifically, several mediators have been proposed, such as diacylglycerols, ceramides, peroxisome proliferator-activated receptors (PPAR), inflammatory kinases and reactive oxygen species (ROS), but their relative contributions to the onset of insulin resistance and their putatively synergistic actions are topics of controversy. Second, there are also pieces of evidence that lipids can induce contractile dysfunction independently of insulin resistance. Perhaps, a more integrative view is needed, in which several lipid-induced pathways operate synergistically or in parallel to induce contractile dysfunction. Unraveling of these processes is expected to be important in designing effective therapeutic strategies to protect the lipid-overloaded heart.

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PPARs: Protectors or Opponents of Myocardial Function?

Cited by 41 publications

References 228 publications

PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects

PPARγ deacetylation dissociates thiazolidinedione’s metabolic benefits from its adverse effects

A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction

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