Matrix Metalloproteinase-7 and ADAM-12 (a Disintegrin and Metalloproteinase-12) Define a Signaling Axis in Agonist-Induced Hypertension and Cardiac Hypertrophy

Abstract

Background-Excessive stimulation of Gq protein-coupled receptors by cognate vasoconstrictor agonists induces a variety of cardiovascular processes, including hypertension and hypertrophy. Here, we report that matrix metalloproteinase-7 (MMP-7) and a disintegrin and metalloproteinase-12 (ADAM-12) form a novel signaling axis in these processes. Methods and Results-In functional studies, we targeted MMP-7 in rodent models of acute, long-term, and spontaneous hypertension by 3 complementary approaches: (1) Pharmacological inhibition of activity, (2) expression knockdown (by antisense oligodeoxynucleotides and RNA interference), and (3) gene knockout. We observed that induction of acute hypertension by vasoconstrictors (ie, catecholamines, angiotensin II, and the nitric oxide synthase inhibitor N G -nitro-

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.…”

“…The involvement of MMP-7 in vascular tone regulation is supported by studies of small mesenteric arteries from MMP-7 knock-out and knock-down (i.e. siRNA) mouse models that display resistance to Ang II and norepinephrine-induced acute hypertension as well as cardiac hypertrophy and fibrosis [31]. Furthermore, pharmacological inhibition of ADAM-12 blocks shedding of HB-EGF thus attenuating cardiac hypertrophy, but not hypertension [4].…”

“…However, an upregulation of MMP-2 expression in mice with Ang II-induced hypertension may have negligible effects on the development of cardiac hypertrophy and fibrosis induced by short-term (over 14 days) Ang II infusion [42]. Gene knock-out, siRNA and pharmacological inhibition of MMP-7 in mice, prevent Ang IIinduced ADAM-12 overexpression as well as cardiac hypertrophy [31]. Indeed, Ang II induces an upregulation of ADAM-12 that mediates hypertrophic processes in the heart [4].…”

“…Indeed, following the administration of Ang II to mice, vascular (aortic) MMP-7 (but not MMP-2) may be acutely activated (within one hour). Lack of acute detectable activation of pro-MMP-2 (72 kDa) to yield MMP-2 (62 kDa) indicates that basal MMP-2 may be engaged in agonist-induced processes [31]. Studies show that broad-spectrum blockade of MMPs (using doxycycline) as well as a biphenylsulfonamido-hydroxamate inhibitor selective for MMP-2 (MMP-2 inhibitor III, Calbiochem) relaxes phenylephrine pre-constricted small mesenteric arteries [42].…”

“…For instance, several days after Ang II infusion begins through minipumps, cardiac MMP-7 and MMP-9 mRNA levels are found to decrease [31]. By contrast, the mRNA levels of MMP-2 and ADAM-12 are strongly upregulated [31].…”