Cardioprotective effects of peroxisome proliferator activated receptor gamma activators on acute myocarditis: anti-inflammatory actions associated with nuclear factor kappaB blockade.

Abstract

OBJECTIVE:

To test the hypothesis that activation of peroxisome proliferator activated receptor gamma (PPAR-gamma) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor kappaB (IkappaB) alpha induction, blockade of nuclear factor kappaB (NF-kappaB), and inhibition of inflammatory cytokine expression.

METHODS:

EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-gamma activators 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administered to rats with EAM.

RESULTS:

Enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-gamma activators enhanced IkappaB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-kappaB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups.

CONCLUSIONS:

PPAR-gamma may have a role in the pathophysiology of EAM. Because an increase in IkappaB expression and inhibition of translocation of the NF-kappaB subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-gamma activators, these results suggest that PPAR-gamma activators act sequentially through PPAR-gamma activation, IkappaB induction, blockade of NF-kappaB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-gamma activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.

• Authors: Z Yuan, Y Liu, Y Liu, J Zhang, C Kishimoto, Y Wang, A Ma, Z Liu
• Journal: Heart (British Cardiac Society) (Heart) Vol. 91 Issue 9 Pg. 1203-8 (Sep 2005) ISSN: 1468-201X [Electronic] England
• PMID: 15774612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 15-deoxyprostaglandin J2
• Cardiotonic Agents
• Cytokines
• NF-kappa B
• PPAR gamma
• RNA, Messenger
• Thiazolidinediones
• Myosins
• Prostaglandin D2
• Pioglitazone

Topics

• Acute Disease
• Animals
• Autoimmune Diseases (chemically induced, drug therapy, metabolism)
• Cardiotonic Agents (therapeutic use)
• Cytokines (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Myocarditis (chemically induced, drug therapy, metabolism)
• Myosins
• NF-kappa B (antagonists & inhibitors, metabolism)
• PPAR gamma (metabolism)
• Pioglitazone
• Prostaglandin D2 (analogs & derivatives, therapeutic use)
• RNA, Messenger (genetics)
• Rats
• Rats, Inbred Lew
• Thiazolidinediones (therapeutic use)