Abstract 431: Signal Transducer and Activator of Transcription 3 Contributes to Angiotensin II-Induced Left Ventricular Hypertrophy In Vivo
The transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the hypertrophic response of cultured cardiomyocytes; however, its precise function in the hypertrophic process in vivo is unknown. Here we characterized the role of STAT3 in pressure overload-induced left ventricular (LV) hypertrophy. Male Sprague-Dawley rats were infused with vehicle or angiotensin II (Ang II) at a pressor dose (33 μg/kg/h) via subcutaneously implantated osmotic minipumps for 1 week in the presence and absence of parthenolide (0.5 mg/kg/day, i.p.), an inhibitor of STAT3. Western blot analysis revealed that Ang II infusion for 1 week increased the phosphorylation of Janus kinase 2 (JAK2) on Tyr1007/1008 (1.5-fold, P<0.01), the upstream activator of STAT proteins, and STAT3 on Tyr705 (1.6-fold, P<0.05) and Ser727 (1.7-fold, P<0.01). Administration of parthenolide abolished tyrosine and serine phosphorylation of STAT3 (P<0.05), while JAK2 phosphorylation was not altered (P=NS). Infusion of Ang II for 1 week increased LV weight/body weight ratio by 34±6% (P<0.001), which was significantly attenuated by parthenolide (13±3% increase, P<0.05). Echocardiography demonstrated that LV systolic function was preserved in Ang II +parthenolide treated animals despite the reduction in LV mass. Northern blot analysis showed that parthenolide significantly decreased the Ang II-induced increases in the mRNA levels of atrial natriuretic peptide (17.2-fold vs. 8.3-fold; Ang II vs. Ang II +parthenolide; P<0.05), collagen I (5.2-fold vs. 1.6-fold; P<0.01), and fibronectin (5.3-fold vs. 2.3-fold; P<0.05). In contrast, the mRNA levels of B-type natriuretic peptide (2.5-fold vs. 2.0-fold; P=NS) and skeletal alpha-actin (2.5-fold vs. 2.4-fold; P=NS) were not affected significantly. In summary, our work presents an in vivo evidence for a critical role of STAT3 signaling in the hypertrophic process. Our results demonstrate that selective inhibition of STAT3 activation prevents LV hypertrophy and fibrosis without compromising cardiac function. Thus, the suppression of STAT3 signaling appears to be a potential therapeutic strategy targeting the maladaptive features of cardiac hypertrophy.