Effects of angiotensins on cellular hypertrophy and c‐fos expression in cultured arterial smooth muscle cells

Abstract

An increase in cell size and protein content was observed when quiescent arterial smooth muscle cells in culture were incubated with either angiotensin I1 or 111. These effects were inhibited by the specific angiotensin type-1 receptor antagonist losartan (DuP 753) but not by CGP 421 12A. In parallel, a transient and dose-dependent induction of czfos was demonstrated not only with angiotensins I1 and I11 but also with angiotensin I. Both angiotensins I1 and 111 exerted their maximal effect at 1 pM, while angiotensin I needed a tenfold-higher concentration to exert an identical effect. As for hypertrophy, losartan also inhibits angiotensin-induced c-fos expression, suggesting that this gene may be involved into the hypertrophic process. Angiotensin-I-mediated c-jos induction is partially inhibited by the angiotensin-converting enzyme inhibitors captopril and trandolaprilate; given that an angiotensin-converting enzyme activity was detected in these smooth muscle cell cultures, these results suggest that angiotensin-I-induced c-fos expression is mediated in part via angiotensin-I conversion to angiotensin 11, but also by other unidentified pathway(s). Angiotensin I could essentially induce smooth muscle cell hypertrophy by indirect mechanisms, while angiotensins I1 and 111 act directly on smooth muscle cells.The effect of hypertension on the arterial wall is characterized by an increase in smooth muscle mass due to cellular hypertrophy and/or hyperplasia (for review, see [l]). In chronic hypertension models such as spontaneously hypertensive rats (SHR) or two-kidney one-clip Goldblatt hypertensive rats, the increased mass of smooth muscle cells (SMC) in aortas is due principally to SMC hypertrophy [2-41. In contrast, an increase in medial SMC number, resulting from their proliferation, is accounted for by the increase in smooth muscle mass in models of acute severe hypertension such as aortic coarctation [5, 61. Factors inducing in vivo arterial SMC hypertrophy are not yet well defined. However, some reports suggest that the vasoconstrictor peptide angiotensin (Ang) I1 may play a role in this induction. Indeed, administration of angiotensin-converting enzyme (ACE) inhibitors decreases SMC hypertrophy in the aorta of SHR during the development of hypertension. As this effect is not entirely mediated by reduction in blood pressure, it has been postulated that local angiotensin may participate in the development of SMC hypertrophy [7, 81. In vitro data corroborate the role of AngII in SMC hypertrophy, since AngII induces an increase in cell volume and protein content in quiescent aortic SMC in culture [9 -111. In addition

Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy.

“…These results are similar to those in a recent report on rat SMCs. 13 The signal transduction mechanisms for Ang II-induced hypertrophic responses are not completely understood. Ang II can activate a phosphatidylinositol-specific phospholipase C leading to inositol trisphosphate, which can mobilize calcium.…”

AT1 receptor characteristics of angiotensin analogue binding in human synovium

“…Binding to each structure was of high affinity, and no significant differences were found between structures in association and dissociation rates, nor in Kd values (Table 2). (Whitebread et al, 1989;Dudley et al, 1990;Weinstock et al, 1991;Bottari et al, 1991 (Urata et al, 1989) and on cultured vascular smooth muscle cells (Whitebread et al, 1989) and are believed to mediate vasoconstriction (Chiu et al, 1990) and smooth muscle hypertrophy (Millet et al, 1992), both of which may reduce tissue perfusion. Synovial hypoperfusion has been implicated in the pathogenesis of human arthritis (Levick, 1990), and the potential of AT, antagonists to enhance tissue perfusion (Azuma et al, 1992) (Whitebread et al, 1989;Patel et al, 1989).…”

Acute intrarenal infusion of ANG II does not stimulate immediate early gene expression in the kidney

“…Upregulation of egr-1 mRNA and protein after incubation with ANG II has been demonstrated in a number of cell culture systems, including vascular smooth muscle cells (8,30,33). Likewise, expression of c-fos mRNA has been shown to be upregulated by ANG II in cultured rat cardiomyocytes and smooth muscle cells (16,22,25). Activation of the AT 1 receptor by ANG II initiates multiple signal transduction pathways, including G protein-coupled phospholipases and some tyrosine kinase pathways that are also coupled to growth factor receptors (13).…”

“…The expression of both of these genes reaches a maximum at 30-60 min and then declines to basal levels by ϳ2-4 h (8,14,16,20,22,23,25,27,28,30,33,35,39). Although we cannot rule out the possibility that a peak response in early gene expression may have occurred beyond the 30-min time point, yet before the 240-min time point, we chose to look for expression at 30 min based on the findings of ANG II-induced early gene expression in cultured cells.…”

“…kidney; blood pressure; c-fos; egr-1; renal blood flow ANG II IS KNOWN to stimulate both hypertrophy and proliferation of vascular smooth muscle cells in culture (5,11,12,32) and has also been reported to stimulate expression of early growth response genes such as early growth response gene-1 (egr-1; zif-268) and c-fos (18,22,33,35). Likewise, ANG II has trophic actions on many cells of renal origin in culture, including renal arteriolar smooth muscle cells (8,(40)(41)(42)(43).…”