Abstract 9889: A Potent Flavonoid Luteolin Protects Against the Angiotensin II-Induced Cardiac Remodeling

Abstract

Background: Luteolin is a food-derived flavonoid and its antioxidant, anti-inflammatory, and antifibrotic functions are reported. However, the effects of luteolin on the cardiac remodeling remain to be clarified.

Methods: Five-week-old male rats were divided into 3 subgroups; 1) Ang II+Luteolin- rats which fed with normal diet for 3 weeks and then infused with angiotensin II (Ang II; 0.7 mg/kg/min) for 1 week with an osmotic mini-pump, 2) Ang II+Luteolin+ rats which fed with 0.035% luteolin-mixed diet for 3 weeks and then infused with Ang II for 1 week with an osmotic mini-pump, 3) Control rats which fed with normal diet for 3 weeks and then received the sham operation. The effect of oral luteolin administration on the cardiac remodeling was evaluated by echocardiography, histopathology and Real-time PCR technique. In vitro, cultured human cardiac fibroblasts (HCFs) were pretreated with luteolin or PBS before the stimulation with Ang II. The influence of luteolin pretreatment on the expression levels of related genes and the phosphorylation of c-JUN NH2-terminal protein kinase (JNK1) and extracellular signal-regulated kinase 1/2 (ERK1/2) were evaluated.

Results: Systolic blood pressure was higher in both Ang II+Luteolin- rats and Ang II+Luteolin+ rats, compared with control rats. Echocardiography revealed accelerated cardiac concentric remodeling in Ang II+Luteolin- rats, but not in Ang II+Luteolin+ rats. Left ventricular weight was lower in Ang II+Luteolin+ rats than that in Ang II+Luteolin- rats (p=0.031). Histopathologic studies showed less prominent interstitial fibrosis in the ventricles of Ang II+Luteolin+ rats than in those of Ang II+Luteolin- rats. Cardiac gene expression levels of atrial natriuretic peptides and transforming growth factor-β1 (TGF-β1) were significantly suppressed in Ang II+Luteolin+ rats, compared with Ang II+Luteolin- rats. In cultured HCFs, luteolin pretreatment significantly inhibited the Ang II-induced upregulation of phosphorylated JNK1 and phosphorylated ERK1/2.

Conclusion: Oral administration of luteolin has a protective role against Ang II-induced cardiac remodeling through suppression of the Ang II-TGF-β1 signaling pathway, which can be related to suppression of JNK1 and ERK1/2 pathways.