Ethanol And Smooth Muscle Cell Proliferation

Excessive proliferation of arterial SMC plays an important role in the process of atherogenesis and hypertension [14], Therefore, inhibition and stimulation of VSMC proliferation may be crucial for preventing and exacerbating, respectively, the development of cardiovascular disease. One key regulatory enzyme pathway for control points within the cell cycle has been identified as mitogen-activated protein kinases (MAPKs) [51], They are serine/threonine protein kinases that are activated by dual phosphorylation ofboth tyrosine and threonine residues. Highly conserved during eukaryotic evolution, they are rapidly activated in response to ligand binding by both growth factor receptors with intrinsic tyrosine kinase activity, such as the platelet derived growth factor (PDGF) receptor, and receptors that are coupled to G-proteins such as the thrombin receptor [51-53], They are also activated by hemodynamic stimuli [11]. Members of the MAPK family include the ERKs (ERK-1 and

ERK-2) which are activated by MEK (also referred to as MAPK kinase). MEK itself is activated by phosphorylation on two conserved serine residues by Ser/Thr kinases such as Raf, Mos and Mek kinase (MEKK) [54], ERKs are dephosphorylated and inactivated by MAPK phosphatase-1 (MKP-1). Several studies have provided compelling evidence for a role of MAPKs in regulating SMC growth [55], MAPK signaling, in particular ERK activity, is increased in rat carotid arteries following balloon injury concomitant with enhanced medial cell proliferation [56], Furthermore, inhibition ofMAPK signaling with PD 098059, a MEK inhibitor, reduced medial cell replication following injury [56], MKP-1 expression is high in normal arterial tissue, whereas ERK expression is low [55,57], However, following balloon injury the expression ofMKP-1 decreases dramatically, whereas that of ERK is increased [57], In proliferating cells it has been postulated that activated ERK-MAPKs phosphorylate specific cytoplasmic and nuclear proteins needed for passage through certain checkpoints in the cell cycle (e.g., Gl/S and G2/M) [58],

The effect of ethanol on MAPK in VSMC in vitro has been investigated and divergent effects reported. Hendrickson et al. demonstrated that ethanol treatment (24 h), at physiologically relevant concentrations, inhibited serum-stimulated growth and MAPK activity in cultured SMC in the absence of any effect on cell viability (Figure 9.5) [59], The mechanism of ethanol's induced changes in smooth muscle MAPK signaling and growth remain unclear. The decreased phosphorylation ofERK-1 and ERK-2 by MEK in cells exposed to ethanol suggests that MEK inhibition determines ERK inhibition by ethanol in these cells. Several studies have demonstrated that ethanol can inhibit the proliferation of cells at the level of growth factor receptor expression [60], Ethanol inhibited basic fibroblast growth factor (bFGF)-induced proliferation of C6 astrocytoma cells [61], In addition, ethanol markedly inhibited cell growth stimulation in response to insulin like growth factor-1 (IGF-1) and depressed tyrosine phosphorylation of the IGF-1 receptor [60], Since ethanol induces G1 phase arrest in SMC in vitro, it is possible that inhibition of specific growth factor receptor autophosphorylation may in part account for the antiproliferative effects of ethanol in SMC. However, Sachinidis et al. demonstrated that ethanol had a different effect on SMC depending on the exposure time used. In their hands, acute treatment of VSMC with ethanol (3-5 min) led to a substantial increase in DNA synthesis and stimulated the same intracellular signalling events (including PIP2 hydrolysis, MAPK activation, and stimulation of c-fos mRNA expression) associated with the potent growth factors PDGF-BB and Angiotensin II, whereas more chronic treatment (>30 min) resulted in cell necrosis [62], Changes in intravascular hemodynamic forces that occur in disease states such as hypertension are profoundly associated with remodeling of the vascular media. Several studies have confirmed that subjecting SMC to increased pressure and/or stretch, in the absence of a functional endothelium, can result in increased wall thickness in vivo and proliferation of SMC in vitro [63,64], Under normal circumstances in adult organisms, the vascular system functions in a relatively quiescent state despite these forces impacting on the vascular smooth muscle [8], In contrast, following vascular injury due to endothelial dysfunction or denudation, SMC abandon their quiescent state and actively proliferate under the influence of mitogenic and other factors [65], Several studies have demonstrated a marked heterogeneity of SMC phenotypes in rodents and humans [66,67], Intimal SMC associated with vascular remodeling following injury are phenotypically distinct from their medial counterparts [66,67], Characteristically, intimal cells resemble immature, dedifferentiated SMC and have lower levels of contractile proteins, fewer

Figure 9.5 The effect of ethanol on smooth muscle cell proliferation. Ethanol (24-h exposure) dose-dependently inhibits (a) SMC 3H-Thymidine incorporation, and (b) MAPK activity, determined by measuring phosphorylated ERK-1 and ERK-2. (Reproduced by permission ofElsevier Science from Hendrickson et al. (1998), [59]).

Figure 9.5 The effect of ethanol on smooth muscle cell proliferation. Ethanol (24-h exposure) dose-dependently inhibits (a) SMC 3H-Thymidine incorporation, and (b) MAPK activity, determined by measuring phosphorylated ERK-1 and ERK-2. (Reproduced by permission ofElsevier Science from Hendrickson et al. (1998), [59]).

myofilaments and express a large number of proteins involved in lesion development [66,67], In contrast, medial SMC express differentiated cell markers associated with contractile function (a-actin, myosin, calponin and phospholamban) and the synthesis and maintenance of extracellular components of the vessel wall (e.g., osteopontin, elastin). Cappadona et al. demonstrated that SMC phenotype is a critical determinant of the proliferative response of SMC to hemodynamic forces [68], in that phenotypically distinct cells respond negatively to pulse pressure in a MAPK-dependent manner. Interestingly, in a recent study using rabbit iliac arteries following balloon angioplasty, significant inhibition of SMC phenotype conversion from contractile to synthetic was observed following ethanol treatment that was indicative of an inhibition of SMC proliferation [69], Moreover, ethanol treatment at low concentrations results in inhibition of SMC growth in a MAPK-dependent manner [59], Further investigation of the effect of ethanol on SMC phenotype and how the differentiation state of these cells affect hemodynamic force-induced signaling and growth in SMC is warranted.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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