Tumor Necrosis Factor-α–Converting Enzyme Is a Key Regulator of Agonist-Induced Cardiac Hypertrophy and Fibrosis

Abstract

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-␣-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 (␣-skeletal actin, ␤-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. Key Words: cardiac hypertrophy Ⅲ hypertension Ⅲ metalloproteinase Ⅲ ADAM-17/TACE Ⅲ Gq protein-coupled receptor agonist Ⅲ RNA interference C ardiac remodeling is a major hallmark of hypertensive disorders and is associated with the development of cardiac hypertrophy (ie, an increase in cell size of individual cardiomyocytes), which causes thickening of the myocardium. Although initially compensatory, sustained hypertrophic growth is pathological, in part, because of its association with the development of fibrosis (ie, increased synthesis and deposition of extracellular matrix proteins), which disrupts the normal structure and contractile properties of the myocardium. 1 Pathological cardiac remodeling is, thus, detrimental for cardiac function and may cause cardiac dysfunction, myocardial stiffness, and increased risk of heart failure, sudden death, and stroke. 2-5 However, it remains unclear how and why such apparently distinct processes as cardiac hypertrophy and fibrosis develop with hypertension and whether pressure overload in hypertension is causal.Our laboratory is investigating the general hypothesis that cardiac remodeling may be associated with hypertens...

The Role of SnoN in Transforming Growth Factor β1-induced Expression of Metalloprotease-Disintegrin ADAM12

“…ADAM12 expression is also markedly up-regulated in cancers of the liver, lung, stomach, colon, prostate, bladder, and in glioblastoma (13)(14)(15)(16)(17)(18). Increased ADAM12 expression levels are found in the cardiac tissue of patients with hypertrophic obstructive cardiomyopathy (19) and in mice with angiotensin II-induced hypertension and cardiac hypertrophy (20,21). During inflammatory responses and aseptic osteolysis associated with loosened hip replacement implants, ADAM12 is up-regulated in the interface tissue around loosening implants (22).…”

Metalloproteinases: key and common mediators of multiple GPCRs and candidate therapeutic targets in models of hypertensive cardiac disease

“…We have identified MMP-2, MMP-7, ADAM-12 and ADAM-17/TACE as mediators of angiotensin II-induced hypertensive cardiac disease. We have also found that gene expression of these metalloproteinases changes throughout disease development [16,36,[40][41][42]. Moreover, some MMPs and ADAMs (such as MMP-7 and ADAM-17) appear to regulate others (such as MMP-2 and ADAM-12).…”

“…In addition to the transient expression of individual MMPs and ADAMs, we observe the emergence of a novel specialization of functions: MMP-7 and MMP-2 may regulate vascular tone whereas ADAM-17 and ADAM-12 may signal cardiac hypertrophy and fibrosis under transcriptional control of MMP-7 and ADAM-17. This functional specialization is determined by temporal differences in expression and hierarchical relationships among MMPs and ADAMs [16,36,[40][41][42].…”

Metalloproteinases in hypertension and cardiac disease: differential expression and mutual regulation

“…Research using experimental animal models of agonist-induced and spontaneous hypertension suggests that MMPs and ADAMs might regulate one another through transcriptional mechanisms to mediate pro-hypertensive, pro-hypertrophic and pro-fibrotic responses to GqPCR agonists [31,55,56]. Therefore, different MMPs and ADAMs probably contribute to disease development within different time windows through overlapping mechanisms and substrates.…”