The role of Rho A/Rho-kinase pathway on the pathogenesis of pulmonary hypertension secondary to left ventricular dysfunction

  • Dr Zen-Kong Dai, Dept. of Pediatrics, Kaohsiung Medical University, Taiwan
  • Dr Ming-Shin Tan, Dept. of Pediatrics, Kaohsiung Medical University, Taiwan
  • Dr Jong-Hau Hsu, Dept. of Pediatrics, Kaohsiung Medical University, Taiwan
  • Dr Jiunn-Ren Wu, Dept. of Pediatrics, Kaohsiung Medical University, Taiwan
  • Dr Bin–Nan Wu, Dept. of Pediatrics, Kaohsiung Medical University, Taiwan
  • Dr Chaw-Chi Chiu, Dept. of Surgery, Kaohsiung Medical University, Taiwan
  • Dr Shah-Hwa Chou, Dept. of Surgery, Kaohsiung Medical University, Taiwan

    • Rho A/Rho Kinase (ROCK) signaling plays a key role in the pathogenesis of experimental pulmonary hypertension (PH), such as hypoxic PH, and monocrotaline (MCT)-induced PH. In this study, we test whether Rho A/ Rho Kinase signaling was involved in the pathogenesis of PH in aortic banded rats. Four weeks after ascending aortic banding, compared with the sham-operated rats, the aortic banded Wistar rats developed PH (28 ± 3 (Mean ± SE ) mmHg, n=8; and 13 ± 1 mmHg, n=8, p<0.01) with medial hypertrophy in pulmonary arteriole. Compared with in sham-operated rats, there were increases in ratio of membrane RhoA /cytosolic RhoA (1.0 ± 0.08, 1.5 ± 0.16, p<0.05) and in ROCK II protein (1.0 ± 0.3; 2.1 ± 0.2, p<0.01 ), respectively, in lungs of banded rats, In extralobar pulmonary arteries, we could detect cleaved (constitutive active) ROCK I, as well as increase in ratio of membrane RhoA/cytosolic Rho A (1.0 ± 0.2; 2.4 ± 0.3, p<0.01) and in ROCK II protein (1.0 ± 0.3; 1.9 ± 0.2, p<0.01) in banded rats, respectively. In addition, there were increased phosphorylated ERM (ezrin, radixin, and moesin) at T567 (ezrin), T5648 (radixin), and T558 (moesin) in lungs of banded rats. Interestingly, the Rho kinase inhibitor, Fasudil (10 mg/kg/iv, within 5 min) could significantly decrease the mean pulmonary arterial pressure (P<0.01), without any change of systemic arterial pressure detected. However, these results suggest that the activation of Rho A/ROCK signaling is involved in the development of PH secondary to left ventricular dysfunction.