The relationship between the MMP system, adrenoceptors and phosphoprotein phosphatases

Abstract

The MMPs and their inhibitors [tissue inhibitor of MMPs (TIMPs) ] form the mainstay of extracellular matrix homeostasis. They are expressed in response to numerous stimuli including cytokines and GPCR activation. This review highlights the importance of adrenoceptors and phosphoprotein phosphatases (PPP) in regulating MMPs in the cardiovascular system, which may help explain some of the beneficial effects of targeting the adrenoceptor system in tissue remodelling and will establish emerging crosstalk between these three systems. Although α‐ and β‐adrenoceptor activation increases MMP but decreases TIMP expression, MMPs are implicated in the growth stimulatory effects of adrenoceptor activation through transactivation of epidermal growth factor receptor. Furthermore, they have recently been found to catalyse the proteolysis of β‐adrenoceptors and modulate vascular tone. While the mechanisms underpinning these effects are not well defined, reversible protein phosphorylation by kinases and phosphatases may be key. In particular, PPP (Ser/Thr phosphatases) are not only critical in resensitization and internalization of adrenoceptors but also modulate MMP expression. The interrelationship is complex as isoprenaline (ISO) inhibits okadaic acid [phosphoprotein phosphatase type 1/phosphoprotein phosphatase type 2A (PP2A) inhibitor]‐mediated MMP expression. While this may be simply due to its ability to transiently increase PP2A activity, there is evidence for MMP‐9 that ISO prevents okadaic acid‐mediated expression of MMP‐9 through a β‐arrestin, NF‐κB‐dependent pathway, which is abolished by knock‐down of PP2A. It is essential that crosstalk between MMPs, adrenoceptors and PPP are investigated further as it will provide important insight into how adrenoceptors modulate cardiovascular remodelling, and may identify new targets for pharmacological manipulation of the MMP system.

Recombinant Human Matrix Metalloproteinase‐2 Impairs Cardiovascular β‐Adrenergic Responses

“…However, this suggestion may not be true in animal models of disease conditions. Matrix metalloproteinases, particularly MMP-2, are known to affect b 1 -and b 2 -adrenoreceptors [21][22][23][24]. The significant attenuation in dobutamine-induced reduction in SVRI after the infusion of rhMMP-2 is consistent with impaired b 2 -adrenoreceptors-mediated vasodilation possibly resulting of enhanced MMP-2 activity.…”

“…Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b 1 -and b 2 -adrenoreceptors [21]. Rodrigues et al [22] demonstrated that the labelling density of the extracellular domain of b 2 -adrenergic receptor in aortic endothelial cells from Wistar rats was reduced after treatment with plasma of spontaneously hypertensive rats with increased MMPs levels, thus indicating cleavage of b 2 -adrenergic receptors.…”

“…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[13], calcitonin gene-related peptide [14] and adrenomedullin [15]. 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][17][18][19][20].Recent studies indicate that MMPs, including MMP-2, are involved in proteolytic cleavage of b 1 -and b 2 -adrenoreceptors [21]. Rodrigues et al [22] demonstrated that the labelling density of the extracellular domain of b 2 -adrenergic receptor in aortic endothelial cells from Wistar rats was reduced after treatment with plasma of spontaneously hypertensive rats with increased MMPs levels, thus indicating cleavage of b 2 -adrenergic receptors.…”

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

“…Other than TIMPs (reviewed in Rietz and Spiers 45 and Brew and Nagase 46 ), little is known about endogenous inhibitors of MMP-9. We reported previously that inflammatory factors such as cytokines and PGE2 induce DC-derived MMP-9 and migration and that endogenous agents such as IFN-␤ inhibit DC migration partially through the transcriptional suppression of Mmp9.…”

Metaloproteinasas de la matriz extracelular y su participación en el proceso de cicatrización

“…Generalmente, las proenzimas son activadas en situaciones donde sea requerida exclusivamente la degradación de la MEC. Algunas citocinas como interleucina 4 y interleucina 13 son antiinflamatorias y por lo tanto, pueden ejercer funciones inhibitorias de las MMPs, principalmente de su forma latente 48 .…”