title: p38α MAPK inhibits stretch-induced JNK activation in cardiac myocytes through MKP-1.
abstract: Mechanical stretch is a major determinant that leads to heart failure, which is associated with a steady increase in myocardial angiotensinogen (Aogen) expression and formation of the biological peptide angiotensin II (Ang II). c-jun NH2-terminal kinase (JNK) and p38α have been found to have opposing roles on stretch-induced Aogen gene expression in neonatal rat ventricular myocytes (NRVM). JNK negatively regulated Aogen expression in NRVM following acute stretch, whereas with prolonged stretch, JNK phosphorylation was downregulated and p38α was found responsible for upregulation of Aogen expression. However, the mechanisms responsible for regulation of these kinases, especially the cross-talk between p38 and JNK1/2, remain to be determined. In this study, a combination of pharmacologic and molecular approaches (adenovirus-mediated gene transfer) were used to examine the mechanisms by which p38 regulates JNK phosphorylation in NRVM under stretch and non-stretch conditions. Pharmacologic inhibition of p38 significantly increased JNK phosphorylation in NRVM at 15 min, whereas overexpression of wild-type p38α significantly decreased JNK phosphorylation. While p38α overexpression prevented stretch-induced JNK phosphorylation, pharmacologic p38 inhibition abolished the JNK dephosphorylation during 15-60 min of stretch. Expression of constitutively-active MKK3 (MKK3CA), the upstream activator of p38, abolished JNK phosphorylation in both basal and stretched NRVM. Pharmacologic inhibition of MAP kinase phosphatase-1 (MKP-1) or protein phosphatase-1 (PP1) increased JNK phosphorylation in NRVM, suggesting the involvement of these phosphatases on reversing stretch-induced JNK activation. Inhibition of MKP-1, but not PP1, reduced JNK phosphorylation in NRVM overexpressing MKK3CA under basal conditions (no-stretch). Inhibition of MKP-1 also enhanced stretch-induced JNK phosphorylation in NRVM at 15 to 60 min. In summary, these results indicate that MKP-1 inhibits JNK phosphorylation in stretched NRVM through p38 dependent and independent mechanisms, whereas PP1 regulates JNK through a p38-independent mechanism.
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Fnu
authors.initials: F
authors.lastname: Gerilechaogetu
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Honey B
authors.initials: HB
authors.lastname: Golden
authors.affiliation: Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Damir
authors.initials: D
authors.lastname: Nizamutdinov
authors.affiliation: Central Texas Veterans Health Care System, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Foster
authors.affiliation: Central Texas Veterans Health Care System, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States; Division of Gastroenterology, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States.
authors.forename: Shannon S
authors.initials: SS
authors.lastname: Glaser
authors.affiliation: Central Texas Veterans Health Care System, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States; Department of Medical Physiology, Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, 1901 South 1st Street, Temple, TX 76504, United States. Electronic address: ddostal@medicine.tamhsc.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001696:Biomechanical Phenomena; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D048308:Mitogen-Activated Protein Kinase 14 / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D048031:JNK Mitogen-Activated Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat
keywords: Cardiac myocytes; JNK; MKP-1; Mechanical stretch; PP1; p38