Ca2+ channel blockers modulate metabolism of collagens within the extracellular matrix.

Abstract

The Cell biological changes during the development of sclerotic lesions are characterized by an increased deposition of extracellular matrix (ECM) proteins such as laminin, fibronectin, and collagens (1-3). The latter represent a family of proteins with at least 14 different members, which form the major structural part of the ECM (4). The ECM has been previously considered to be a relatively inert mass of proteins. However, recent reports have shown that it is subjected to a continuous turnover that accounts for a remodeling of -5-15% of total ECM per day (5). The ECM influences cell functions and is essentially involved in tissue-typespecific gene expression and proliferation (6-8). It is able to affect the differentiation state of a cell, and, consequently, alterations of the composition of the ECM modulate the responsiveness of cells to physiological stimuli such as growth factors, hormones, and cytokines (7). In addition, changes in the relative proportions of components of the ECM are apparently of crucial relevance for the pathogenesis of various diseases such as atherosclerosis (6, 9, 10). Here, the prominence of collagen as a major element of atherosclerotic plaques is well established, taking into account that 90% of the total collagen found in these lesions is formed by collagens type I and III (1). Furthermore, an increased expression of collagens IV, V, and VI was reported in human atherosclerotic plaques (1, 2).ECM metabolism is tightly regulated by a complex network of interactions, including (i) the de novo synthesis of compounds by interstitial cells; (ii) the degradation of existing ECM molecules by the action of various proteases, including members of the matrix metalloprotease (MMP) family; and (iii) the inhibition of protease activities by specific endogenous antagonists such as the tissue inhibitors of metalloproteinases (TIMPs) (11)(12)(13) (17,18). Fibroblasts were cultivated in RPMI 1640 medium supplemented with 10% fetal calf serum and 8 mM stabilized L-glutamine; VSMCs were cultivated in DMEM supplemented with 5% colostrum, 20 mM Hepes, and 8 mM L-glutamine. Subconfluent cultures (80% confluence) were used between passages two and six. Cells were synchronized by starvation for 48 hr in low-serum medium (0.1% fetal calf serum), replacing the medium every 24 hr. Quiescent cells were challenged with human recombinant PDGF BB (10 ng/ml; GIBCO/BRL) in the presence or absence of the drugs.

Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment

“…13 Amlodipine has been demonstrated to increase the proteolytic activity of MMP-2 and to inhibit the transcription of TIMP-2 in both fibroblasts and vascular smooth muscle cells. 22 A possible regulatory mechanism of MMP-2 activation could be linked to changes of intracellular calcium concentration. [23][24][25] Nevertheless, the molecular mechanisms of the modifying effects of amlodipine on MMP proteolytic activity need to be elucidated by further studies.…”

Ligand-independent Activation of the Glucocorticoid Receptor by β2-Adrenergic Receptor Agonists in Primary Human Lung Fibroblasts and Vascular Smooth Muscle Cells

“…Cell Culture-Primary cell lines of fibroblasts (n ϭ 3) or VSMC (n ϭ 3) were established from human lung tissue biopsies obtained from patients undergoing lobectomy or pneumectomy, as described previously (21). Fibroblasts were cultivated in RPMI 1640 supplemented with 10% FCS, 8 mM L-glutamine, and 20 mM HEPES.…”

Review of current nonsurgical management of Peyronie's disease

“…33,34 An in vitro study examining the effects of biologic modifiers on fibroblasts derived from Peyronie's plaques demonstrated that verapamil inhibited the proliferation of these cells more than interferon alpha-2b, colchicine, and prostaglandin E. 35 In addition, verapamil and other calcium channel blockers were found to affect cytokine expression associated with early phases of wound healing and inflammation, including platelet-derived growth factor-BB, interleukin-6, and interleukin-8. 34,36 All this work indicated the importance of regulating the balance between matrix biosynthesis and degradation by fibroblasts.…”