Recombinant Human Matrix Metalloproteinase-2 Impairs Cardiovascular β-Adrenergic Responses.

Ferraz, Karina C.; Sousa‐Santos, Ozélia; Neto‐Neves, Evandro M.; Rizzi, Elen; Muniz, Jaqueline J.; Gerlach, Raquel F.; Tanus‐Santos, Jose E.

Growing evidence supports the involvement of matrix metalloproteinases ( MMPs) in the pathogenesis of many cardiovascular diseases. Particularly, imbalanced MMP-2 activity apparently plays a critical role in cardiovascular remodelling. While some studies have suggested that MMP-2 may affect the vascular tone and impair β-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant human MMP-2 (rh MMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during β1-adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rh MMP-2 (220 ng/kg/min. over 60 min.) or vehicle was infused in the lambs, and no significant haemodynamic changes were found. Therefore, we infused dobutamine at 5 μg/kg/min. i.v. (or saline) over 180 min. in lambs that had received the same rh MMP-2 infusion preceded by doxycycline i.v. at 10 mg/kg (or saline). Plasma and cardiac MMP-2 levels were assessed by gelatin zymography, and gelatinolytic activity was assessed by spectrofluorimetry. Dobutamine decreased systemic vascular resistance index, and this effect was attenuated by rh MMP-2 infusion. Moreover, dobutamine increased the cardiac index and left ventricular dP/ dtmax, and these effects were attenuated by rh MMP-2. The previous administration of doxycycline blunted rh MMP-2-induced changes in dobutamine responses. While the infusion of rh MMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our findings show that rh MMP-2 exerts no major haemodynamic effects in lambs. However, rh MMP-2 impairs the responses elicited by activation of β-adrenoreceptors.

MATRIX metalloproteinases; CARDIOVASCULAR diseases; BETA adrenoceptors; DOBUTAMINE; DOXYCYCLINE; CARDIAC output

Basic & Clinical Pharmacology & Toxicology, 2013, Vol 112, Issue 2, p103

1742-7835

Academic Journal

10.1111/bcpt.12001