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Nebivolol‐mediated Inhibition of Nutrient Sensor mTOR‐ and Inflammatory Marker JAK2‐mediated Signaling in Myocardium: Involvement of Angiotensin II Receptors

Nebivolol (Neb) is a highly selective â1‐AR blocker in myocardium. The hypothesis that Neb regulates over‐nutrition and Angiotensin II (Ang II) mediated activation of inflammatory signaling pathways in myocardium was tested both in vivo and in vitro using Zucker Obese (ZO) rats and mouse cardiomyocyte HL‐1cells respectively. 12‐week old ZO and ZL (Zucker Lean) rats were treated with Neb (10 mg/kg/day for 21 days). Analysis using high resolution cine‐MRI showed that compared to ZL rat heart, ZO rat heart had increased septal wall thickness by ~30%, prolonged diastolic relaxation time by ~40%, and reduced diastolic initial filling rate by ~2.5 fold and these effects were reversed by Neb treatment (P<0.05). ZO myocardium exhibited increased phosphorylation of mammalian target for rapamycin (mTOR; pSer2448), p70S6kinase (S6K1: pThr389), ribosomal protein S6 (RPS6: pSer235/236), Jak2 (pTyr1007/1008) and STAT1 (pTyr701) and Neb treatment attenuated these effects (P<0.05). Neb (1μM) could also inhibit Ang II (10nM– 100nM)‐induced phosphorylation of mTOR, S6K1, RPS6, Jak2, and STAT1 in HL‐1 cells (P<0.05). Additionally, Neb reversed the increase of Ang II receptor AT2R expression in ZO myocardium and Ang II‐treated HL‐1 cells (P<0.05). Thus, Neb may provide a new strategy for targeting over‐nutrition and Ang II‐induced inflammatory signaling in heart. (Funded by Forest Laboratories [LP] and NIH R01HL073101 [JRS])