Dataset Information

The peroxisome proliferator-activated receptor ?/? agonist GW0742 has direct protective effects on right heart hypertrophy.

ABSTRACT: Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) ?/? agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPAR?/? is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have investigated the potential of GW0742, a PPAR? agonist, to act directly on the right heart in vivo and what transcriptomic signatures are associated with its actions. Right heart hypertrophy and failure was induced in mice using a pulmonary artery banding (PAB) model. GW0742 was administered throughout the study. Cardiovascular parameters were measured using echocardiography and pressure monitoring. Fibrosis and cellular changes were measured using immunohistochemistry. Transcriptomics were measured using the Illumina MouseRef-8v3 BeadChip array and analyzed using GeneSpring GX (ver. 11.0). PAB resulted in right heart hypertrophy and failure and in increased fibrosis. GW0742 reduced or prevented the effects of PAB on all parameters measured. GW0742 altered a number of genes in the transcriptome, with Angptl4 emerging as the top gene altered (increased) in animals with PAB. In conclusion, the PPAR?/? agonist GW0742 has direct protective effects on the right heart in vivo. These observations identify PPAR?/? as a viable therapeutic target to treat pulmonary hypertension that may complement current and future vasodilator drugs.

SUBMITTER: Kojonazarov B

PROVIDER: S-EPMC4070821 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The peroxisome proliferator-activated receptor β/δ agonist GW0742 has direct protective effects on right heart hypertrophy.

Kojonazarov Baktybek B Luitel Himal H Sydykov Akylbek A Dahal Bhola K BK Paul-Clark Mark J MJ Bonvini Sara S Reed Anna A Schermuly Ralph T RT Mitchell Jane A JA

Pulmonary circulation 20131201 4

Pulmonary hypertension is a debilitating disease with no cure. We have previously shown that peroxisome proliferator-activated receptor (PPAR) β/δ agonists protect the right heart in hypoxia-driven pulmonary hypertension without affecting vascular remodeling. PPARβ/δ is an important receptor in lipid metabolism, athletic performance, and the sensing of prostacyclin. Treatment of right heart hypertrophy and failure in pulmonary hypertension is an emerging target for future therapy. Here we have i ...[more]

PMID: 25006409

Similar Datasets

Project description:Liver insufficiency and damage are major causes of death and disease worldwide and may result from exposure to environmental toxicants, specific combinations or dosages of pharmaceuticals, and microbial metabolites. The generation of reactive intermediates, in particular 4-hydroxynonenal (4-HNE), is a common event in liver damage caused by a variety of hepatotoxic drugs and solvents. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are involved in the transcriptional regulation of lipid metabolism as well as other biological functions. Importantly, we have observed that the PPARbeta/delta-/- mouse is more susceptible to chemically induced hepatotoxicity than its wild-type counterpart, and our objective in this study was to elucidate the mechanism(s) by which PPARbeta/delta confers protection to hepatocytes. We hypothesized that PPARbeta/delta plays a protective role by responding to toxic lipids and altering gene expression accordingly. In support, oxidized-VLDL and constituents including 13-S-hydroxyoctadecadienoic acid (13-S-HODE) and 4-HNE are PPARbeta/delta ligands. A structure-activity relationship was established where 4-HNE and 4-hydroperoxynonenal (4-HpNE) enhanced the activity of the PPARbeta/delta subtype while 4-hyroxyhexenal (4-HHE), 4-oxo-2-Nonenal (4-ONE), and trans-4,5-epoxy-2(E)-decenal did not activate this receptor. Increasing PPARbeta/delta activity with a synthetic agonist decreased sensitivity of hepatocytes to 4-HNE and other toxic agents, whereas inhibition of this receptor had the opposite result. Gene expression microarray analysis identified several important PPARbeta/delta-regulated detoxification enzymes involved in 4-HNE metabolism that are regulated at the transcript level. This research established 4-HNE as an endogenous modulator of PPARbeta/delta activity and raises the possibility that agonists of this nuclear receptor may be utilized to prevent or treat liver disease associated with oxidative damage.

Dataset Information

The peroxisome proliferator-activated receptor ?/? agonist GW0742 has direct protective effects on right heart hypertrophy.

Publications

The peroxisome proliferator-activated receptor β/δ agonist GW0742 has direct protective effects on right heart hypertrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets