Tumor necrosis factor-alpha-converting enzyme is a key regulator of agonist-induced cardiac hypertrophy and fibrosis.
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| 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.
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| Authors | Xiang Wang, Tatsujiro Oka, Fung L Chow, Stephan B Cooper, Jeff Odenbach, Gary D Lopaschuk, Zamaneh Kassiri, Carlos Fernandez-Patron |
| Journal | Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 54 Issue 3 Pg. 575-82 (Sep 2009) ISSN: 1524-4563 [Electronic] United States |
| PMID | 19581512 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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