Chichger Havovi, Vang Alexander, O'Connell Kelly A, Zhang Peng, Mende Ulrike, Harrington Elizabeth O, Choudhary Gaurav
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island;
Am J Physiol Lung Cell Mol Physiol. 2015 Apr 15;308(8):L827-36. doi: 10.1152/ajplung.00184.2014. Epub 2015 Feb 6.
Pulmonary hypertension (PH) eventually leads to right ventricular (RV) fibrosis and dysfunction that is associated with increased morbidity and mortality. Although angiotensin II plays an important role in RV remodeling associated with hypoxic PH, the molecular mechanisms underlying RV fibrosis in PH largely remain unresolved. We hypothesized that PKC-p38 signaling is involved in RV collagen accumulation in PH and in response to angiotensin II stimulation. Adult male Sprague-Dawley rats were exposed to 3 wk of normoxia or hypoxia (10% FiO2 ) as a model of PH. Hypoxic rats developed RV hypertrophy and fibrosis associated with an increase in PKC βII and δ protein expression and p38 dephosphorylation in freshly isolated RV cardiac fibroblasts. Further mechanistic studies were performed in cultured primary cardiac fibroblasts stimulated with angiotensin II, a key activator of ventricular fibrosis in PH. Angiotensin II induced a reduction in p38 phosphorylation that was attenuated following chemical inhibition of PKC βII and δ. Molecular and chemical inhibition of PKC βII and δ abrogated angiotensin II-induced cardiac fibroblast proliferation and collagen deposition in vitro. The effects of PKC inhibition on proliferation and fibrosis were reversed by chemical inhibition of p38. Conversely, constitutive activation of p38 attenuated angiotensin II-induced increase of cardiac fibroblast proliferation and collagen accumulation. PKC βII- and δ-dependent inactivation of p38 regulates cardiac fibroblast proliferation and collagen deposition in response to angiotensin II, which suggests that the PKC-p38 signaling in cardiac fibroblasts may be involved and important in the pathophysiology of RV fibrosis in PH.
肺动脉高压（PH）最终会导致右心室（RV）纤维化和功能障碍，这与发病率和死亡率的增加相关。尽管血管紧张素II在与低氧性PH相关的右心室重塑中起重要作用，但PH中右心室纤维化的分子机制在很大程度上仍未得到解决。我们假设蛋白激酶C（PKC）-p38信号通路参与了PH中右心室胶原积累以及对血管紧张素II刺激的反应。成年雄性Sprague-Dawley大鼠暴露于常氧或低氧（10%氧分数）3周作为PH模型。低氧大鼠出现右心室肥大和纤维化，这与新鲜分离的右心室心肌成纤维细胞中PKC βII和δ蛋白表达增加以及p38去磷酸化有关。在用血管紧张素II刺激的原代培养心肌成纤维细胞中进行了进一步的机制研究，血管紧张素II是PH中心室纤维化的关键激活剂。血管紧张素II诱导p38磷酸化减少，在用PKC βII和δ化学抑制后这种减少减弱。PKC βII和δ的分子和化学抑制消除了血管紧张素II诱导的体外心肌成纤维细胞增殖和胶原沉积。通过p38化学抑制可逆转PKC抑制对增殖和纤维化产生的影响。相反，p38的组成性激活减弱了血管紧张素II诱导的心肌成纤维细胞增殖增加和胶原积累。PKC βII和δ依赖的p38失活调节心肌成纤维细胞对血管紧张素II的增殖和胶原沉积反应，这表明心肌成纤维细胞中的PKC-p38信号通路可能参与并在PH中右心室纤维化的病理生理学中起重要作用。
