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Basic science: Cardiovascular disease basic research
e0072 Cardioprotective effect of β3 adrenocepter agonism in pressure overload induced hypertrophy
  1. Niu Xiaolin,
  2. Zheng Qiangsun,
  3. Zhang Lihua,
  4. He Yong,
  5. Cingolani Oscar,
  6. Bedja Djahida,
  7. Kass David,
  8. Barouch Lili
  1. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xian, China

Abstract

Objective β3-adrenergic receptors (β3-AR) and its downstream signalling are recognised as novel modulators of heart function. We have recently shown impaired cardiac functional compensation in a model of pressure overload. We therefore hypothesised that the selective β3-AR agonist, BRL37344 (BRL), would protect the heart from pressure overload induced cardiac remodelling.

Methods and results C57BL/6J mice underwent transverse aortic constriction (TAC) for 3 weeks, resulting in increased cardiac hypertrophy and dysfunction assessed by echocardiography. 3 weeks of BRL treatment (0.1 mg/kg/day via subcutaneous osmotic infusion pump) starting from 1 day post TAC reduced hypertrophy, with lower heart weight normalised to tibia length (100±4 vs 120±7 mg/cm), LV mass (136±7 vs 163±8 mg), wall thickness (1.08±0.02 vs 1.16±0.02 mm) and systolic dimension (1.36±0.09 vs 12.08±0.23 mm; p<0.05 for all), and completely restored systolic function back to normal (58±2 vs 62±1%; p=NS vs sham, p<0.05 vs TAC). BRL reduced myocyte width by H&E staining, but had no effect on fibrosis scale. These benefits from β3-AR stimulation were associated with increased nitric oxide (NO) production (13.73±1.84 vs 5.03±0.52 μM/mg protein) and suppressed superoxide generation (14017±838 vs 21459±783 CPM/mg tissue; p<0.01 vs TAC for both). Neuronal NO synthase (nNOS) protein expression was up-regulated ∼3 fold by BRL treatment (1.11±0.22 vs 0.39±0.17; p<0.05). More interestingly, the suppressive effect of BRL on superoxide generation was abolished by acute nNOS inhibition by specific nNOS inhibitor N5-(1-imino-3-butenyl)-L-ornithine, monohydrochloride) (L-VNIO).

Conclusions These results are the first to show in vivo the cardioprotective effect of β3-AR specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as a downstream molecule favouring NO and reactive oxygen species (ROS) balance in this pathologic process in the failing heart.

  • Cardioprotective effect
  • β3 adrenoreceptor
  • hypertrophy

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