title: BMP4 inhibits PDGF-induced proliferation and collagen synthesis via PKA-mediated inhibition of calpain-2 in pulmonary artery smooth muscle cells.
abstract: In the present study, we investigated the effect of bone morphogenetic protein 4 (BMP4) on PDGF-induced cell proliferation and collagen synthesis in pulmonary artery smooth muscle cells (PASMCs). Normal human PASMCs were incubated with and without PDGF-BB in the absence and presence of BMP4 for 0.5 to 24 h. The protein levels of collagen-I, p-Smad2/3, p-Smad1/5, and intracellular active TGF-β1, calpain activity, and cell proliferation were then measured. The results showed that BMP4 induced an increase in p-Smad1/5 but had no effect on the protein levels of collagen-I, p-Smad2/3, and intracellular active TGF-β1 and calpain activity in control PASMCs. Nevertheless, BMP4 attenuated increases in cell proliferation and protein levels of collagen-I, p-Smad2/3, and intracellular active TGF-β1 and calpain activity in PASMCs exposed to PDGF-BB. Moreover, BMP4 increased PKA activity and inhibition of PKA prevented the inhibitory effects of BMP4 on PDGF-BB-induced calpain activation in normal PASMCs. The PKA activator forskolin recapitulated the suppressive effect of BMP4 on PDGF-induced calpain activation. Furthermore, BMP4 prevented a PDGF-induced decrease in calpain-2 phosphorylation at serine-369 in normal PASMCs. Finally, BMP4 did not attenuate PDGF-induced increases in cell proliferation, collagen-I protein levels, and calpain activation and did not induce PKA activation and did not prevent a PDGF-induced decrease in calpain-2 phosphorylation at serine-369 in PASMCs from idiopathic pulmonary arterial hypertension (PAH) patients. These data demonstrate that BMP4 inhibits PDGF-induced cell proliferation and collagen synthesis via PKA-mediated inhibition of calpain-2 in normal PASMCs. The inhibitory effects of BMP4 on PDGF-induced cell proliferation, collagen synthesis, and calpain-2 activation are impaired in PASMCs from PAH patients, which may contribute to pulmonary vascular remodeling in PAH.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.|Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Cai
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kovacs
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Sam
authors.initials: S
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia; ysu@augusta.edu.|Department of Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia.|Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, Georgia.|Research Service, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia; and.
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Su
mesh_terms: D000328:Adult; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003094:Collagen / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000201:enzymology / Q000473:pathology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D019814:Myristic Acid / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology*; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D055815:Young Adult; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D055415:Bone Morphogenetic Protein 4; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D019814:Myristic Acid; D010768:Phosphoserine; D005576:Colforsin; D003094:Collagen; D019061:src-Family Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002154:Calpain; C569870:CAPN2 protein, human
keywords: lung; pulmonary hypertension; vascular smooth muscle cells