title: Decorin gene delivery inhibits cardiac fibrosis in spontaneously hypertensive rats by modulation of transforming growth factor-beta/Smad and p38 mitogen-activated protein kinase signaling pathways.
abstract: Fibrosis is the response of heart and other organs to injuries. Excessive fibrosis can cause organ dysfunction or even failure. Transforming-growth factor (TGF)-beta is a cytokine that induces fibroblast proliferation and increases the synthesis of a number of extracellular matrix proteins including collagens. Decorin (DCN) is a natural antagonist of TGF-beta. In the current study, we investigated the potential antifibrotic effects of DCN gene delivery by a recombinant adeno-associated viral (rAAV) vector to inhibit cardiac fibrosis in old, spontaneously hypertensive rats (SHRs), which develop severe cardiac and kidney fibrosis if without intervention. The rAAV-DCN vector was injected (at a dose of 1 x 10(11) vector genomes) via the tail vein into 5-month-old male SHRs, resulting in persistent, stable expression of DCN (up to 16 weeks). rAAV-DCN treatment significantly reduced collagen content and fibrosis in the heart and attenuated cardiomyocyte hypertrophy. Hemodynamics data at 16 weeks showed that DCN gene delivery induced a significant increase in left ventricular end-systolic pressure and maximal-minimal rate of pressure increase (+/-dp/dt(max)), but a decrease in left ventricular end-diastolic pressure (p < 0.05), compared with those of control animals. The expression of TGF-beta and alpha-smooth muscle actin, and the phosphorylation levels of Smad2 and p38 MAPK, were markedly reduced by rAAV-DCN treatment as compared with the controls. Thus, these results suggest that rAAV-mediated DCN overexpression led to the inhibition of hypertension-induced cardiac fibrosis and hypertrophy and improved cardiac function, and therefore may have therapeutic potential for organ fibrosis.
authors.affiliation: Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yan
authors.forename: Peihua
authors.initials: P
authors.lastname: Wang
authors.forename: Chun Xia
authors.initials: CX
authors.lastname: Zhao
authors.forename: Jiarong
authors.initials: J
authors.lastname: Tang
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control; D058575:Decorin; D000229:Dependovirus / Q000187:drug effects / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use*; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007668:Kidney / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011509:Proteoglycans / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D051785:Smad Proteins / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; D020011:Protective Agents; D011509:Proteoglycans; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases