chrysin and Myocardial-Infarction

Pharmacological strategies aimed at co-activating peroxisome proliferator-activated receptor-gamma (PPAR-γ)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway have shown promising results in alleviating myocardial injury. The aim of the study was to evaluate the role of chrysin, a PPAR-γ agonist, in ischemia-reperfusion (IR)-induced myocardial infarction (MI) in rats and to explore the molecular mechanism driving this activity. To evaluate this hypothesis, chrysin (60 mg/kg, orally), PPAR-γ antagonist (GW9662, 1 mg/kg, intraperitoneally), or both were administered to rats for 28 days. On the 29th day, one-stage ligation of left anterior descending coronary artery for 45 min followed by 60 min of reperfusion was performed. Chrysin significantly decreased infarct size and improved cardiac functions following IR-induced MI. This improvement was corroborated by augmented PPAR-γ/Nrf2 expression as confirmed by immunohistochemistry and western blotting analysis. Chrysin exhibited strong anti-oxidant property as demonstrated by increased GSH and CAT levels and decreased 8-OHdG and TBARS levels. Our findings also imply that chrysin significantly inhibited inflammatory response as validated by decreased NF-κB, IKK-β, CRP, TNF-α and MPO levels. In addition, chrysin decreased TUNEL/DAPI positivity, a marker of apoptotic response and normalized cardiac injury markers. The histopathological and ultrastructural analysis further supported the functional and biochemical outcomes, showing preserved myocardial architecture. Intriguingly, co-administration with GW9662 significantly diminished the cardioprotective effect of chrysin as demonstrated by depressed myocardial function, decreased PPAR-γ/Nrf2 expression and increased oxidative stress. In conclusion, the present study demonstrates that co-activation of PPAR-γ/Nrf2 by chrysin may be crucial for its cardioprotective effect.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Cardiovascular Agents; Disease Models, Animal; Flavonoids; Hemodynamics; Inflammation Mediators; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress; PPAR gamma; Rats, Wistar; Signal Transduction; Ventricular Function, Left

Interstitial fibrosis after acute myocardial infarction (MI) leads to cardiac structural remodeling and dysfunction. The peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist chrysin has been shown to protect injured myocardium through suppression of oxidative stress and inflammation. This study was designed to investigate the effect and mechanism of chrysin on myocardial fibrosis. A rat MI model was created by ligating the left coronary artery. The rats with MI were treated with chrysin (40 mg/kg/day) or 0.5% carboxymethylcellulose sodium by intragastric administration for 4 weeks after operation. The effect of chrysin on cardiac fibroblasts (CFs) were also assessed in vitro. Echocardiography showed that cardiac function was significantly improved after chrysin treatment. Chrysin reduced the levels of MDA and SOD and GSH-Px in myocardial tissue. Chrysin attenuated the interstitial and perivascular fibrosis and the expression of collagenlin the peri-infarcted zone and remarkably decreased the levels of matrix metalloproteinase-2 (MMP-2) and MMP-9. Chrysin up-regulated PPAR-γ and inhibited the nuclear factor-kappa B (NF-κB) pathway by suppressing inhibitor kappa B kinase β phosphorylation. Immunohistochemistry analysis and PCR detected downregulated expression of AP-1 after chrysin treatment. Chrysin also markedly reduced the increased α-SMA, typeland type III collagen expression of CFs mediated by AngII in vitro. In conclusion, chrysin has an antifibrosis cardioprotective effect on the infarct peripheral zone after MI. The underlined mechanism may be the up-regulation of PPAR-γ and inhibition of the NF-κB and AP1 pathway.

Topics: Animals; Disease Models, Animal; Fibroblasts; Fibrosis; Flavonoids; Heart; Myocardial Infarction; NF-kappa B; PPAR gamma; Rats; Transcription Factor AP-1; Up-Regulation