title: Tumor necrosis factor-alpha-converting enzyme is a key regulator of agonist-induced cardiac hypertrophy and fibrosis.
abstract: Cardiac remodeling is associated with hypertrophy and fibrosis processes, which may depend on the activity of matrix metalloproteinases (MMPs) and "a disintegrin and metalloproteinases" (ADAMs). We investigated whether ADAM-17 (tumor necrosis factor-alpha-converting enzyme [TACE]) plays a role in agonist-induced cardiac remodeling and the relationships established among TACE, MMP-2, and ADAM-12. We targeted TACE in rodent models of spontaneous and agonist-induced hypertension using RNA interference combined with quantitative RT-PCR, activity determinations, and functional studies. Treatment of spontaneously hypertensive rats with previously validated TACE small-interfering RNA for 28 days resulted in systemic knockdown of TACE expression. TACE knockdown effectively stopped the development of cardiac hypertrophy. Mice receiving angiotensin II (1.4 mg/kg per day for 12 days) exhibited cardiac hypertrophy, as well as fibrosis, which was associated with elevated myocardial expression of molecular markers of hypertrophy (alpha-skeletal actin, beta-myosin heavy chain, and brain natriuretic peptide) and fibrosis (collagen types I and III and fibronectin), as well as MMP-2 and ADAM-12. Treatment with TACE small-interfering RNA (but not with PBS or luciferase small-interfering RNA) inhibited TACE expression, thus preventing angiotensin II-induced cardiac hypertrophy and fibrosis. Moreover, knockdown of TACE inhibited angiotensin II-induced overexpression of markers of myocardial hypertrophy and fibrosis, as well as ADAM-12 and MMP-2. These findings provide the first in vivo evidence that agonist-induced cardiac hypertrophy and fibrosis processes are signaled through TACE, which acts through novel pathways involving transcriptional regulation of ADAM-12 and MMP-2. Targeting TACE has potential therapeutic importance for modulating agonist-induced cardiac remodeling.
authors: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. carlos.fernandez-patron@ualberta.ca
authors: Xiang
authors: X
authors: Wang
authors: Tatsujiro
authors: T
authors: Oka
authors: Fung L
authors: FL
authors: Chow
authors: Stephan B
authors: SB
authors: Cooper
authors: Jeff
authors: J
authors: Odenbach
authors: Gary D
authors: GD
authors: Lopaschuk
authors: Zamaneh
authors: Z
authors: Kassiri
authors: Carlos
authors: C
authors: Fernandez-Patron
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072199:ADAM12 Protein; D000072198:ADAM17 Protein; D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D004452:Echocardiography; D005355:Fibrosis / Q000139:chemically induced; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D011918:Rats, Inbred SHR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000804:Angiotensin II; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C541118:ADAM12 protein, rat; C096115:Adam12 protein, mouse; D020778:Matrix Metalloproteinase 2; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat