Basic & Clinical Pharmacology & Toxicology
Recombinant Human Matrix Metalloproteinase-2 Impairs Cardiovascular b-Adrenergic Responses
Karina C. Ferraz1, Ozélia Sousa-Santos2, Evandro M. Neto-Neves2, Elen Rizzi2, Jaqueline J. Muniz1, Raquel F. Gerlach3 and Jose E. Tanus-Santos2
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas,Campinas, Brazil, 2Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil, and 3Department of Morphology, Stomatology and Physiology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil (Received 28 June 2012; Accepted 9 August 2012) Abstract: Growing evidence supports the involvement of matrixmetalloproteinases (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 b-adrenoreceptor function, no previous study has examined the acute haemodynamic effects of MMP-2. We examined the effects of recombinant humanMMP-2 (rhMMP-2) administered intravenously to anaesthetized lambs at baseline conditions and during b1-adrenergic cardiac stimulation with dobutamine. We used 26 anaesthetized male lambs in two study protocols. First, rhMMP-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 lg/kg/ min. i.v. (orsaline) over 180 min. in lambs that had received the same rhMMP-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 rhMMP-2 infusion. Moreover, dobutamine increasedthe cardiac index and left ventricular dP/dtmax, and these effects were attenuated by rhMMP-2. The previous administration of doxycycline blunted rhMMP-2-induced changes in dobutamine responses. While the infusion of rhMMP-2 did not increase plasma and cardiac MMP-2 levels, it increased cardiac gelatinolytic activity, and doxycycline blunted this effect. Our ﬁndings show that rhMMP-2 exerts nomajor haemodynamic effects in lambs. However, rhMMP-2 impairs the responses elicited by activation of b-adrenoreceptors.
Growing evidence supports the involvement of a group of enzymes named matrix metalloproteinases (MMPs) in the pathogenesis of many disease conditions, including diseases affecting the cardiovascular system [1–4]. Particular attention has been paid to MMP-2 because imbalancedMMP-2 activity apparently plays a critical role in cardiovascular remodelling [5–7] and in other alterations of the cardiovascular system [8– 10]. However, recent studies are clearly showing that MMP-2 may have many other targets unrelated to the extracellular matrix, including intracellular substrates [11,12] and other mediators possibly affecting the vascular tone such as bigendothelin-1,calcitonin gene–related peptide  and adrenomedullin . Importantly, activated MMP-2 has been shown to impair cardiac function possibly as a result of its activity targeting sarcomeric and cytoskeletal proteins such as troponin I, myosin light chain-1, a-actinin and titin [16–20]. Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b1- and b2-adrenoreceptors. Rodrigues et al.  demonstrated that the labelling density of the extracellular domain of b2-adrenergic receptor in aortic endothelial cells from Wistar rats was reduced after treatment with plasma of spontaneously hypertensive rats with
Author for correspondence: Jose E. Tanus-Santos, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av....
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