title: PKC δ and βII regulate angiotensin II-mediated fibrosis through p38: a mechanism of RV fibrosis in pulmonary hypertension.
abstract: 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.
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Havovi
authors: H
authors: Chichger
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island;
authors: Alexander
authors: A
authors: Vang
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Kelly A
authors: KA
authors: O'Connell
authors: Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Peng
authors: P
authors: Zhang
authors: Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island; and Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Ulrike
authors: U
authors: Mende
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island.
authors: Elizabeth O
authors: EO
authors: Harrington
authors: Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Providence, Rhode Island; Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island gaurav_choudhary@brown.edu.
authors: Gaurav
authors: G
authors: Choudhary
mesh_terms: D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology; D005355:Fibrosis; D006352:Heart Ventricles / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000150:complications / Q000201:enzymology*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology*; D008297:Male; D064546:Protein Kinase C beta / Q000502:physiology*; D051745:Protein Kinase C-delta / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D018497:Ventricular Dysfunction, Right / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D003094:Collagen; D064546:Protein Kinase C beta; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases
keywords: PKC; angiotensin II; cardiac fibroblast; p38; pulmonary hypertension; right ventricle