Signaling Events Mediating the Additive Effects of Oleic Acid and Angiotensin II on Vascular Smooth Muscle Cell Migration

Abstract

Abstract-Obese hypertensive patients with cardiovascular risk factor clustering and increased risk for atherosclerotic disease have increased plasma nonesterified fatty acid levels, including oleic acid (OA), and a more active renin-angiotensin-aldosterone system. Vascular smooth muscle cell (VSMC) migration and proliferation participate in the development of atherosclerotic plaque. OA and angiotensin (Ang) II induce synergistic mitogenic responses in VSMCs through sequential signaling pathways dependent on the activation of protein kinase C (PKC), oxidants (reactive oxygen species, ROS), and extracellular signal-regulated kinase (ERK) activation. We tested the hypotheses that (1) OA and Ang II have additive or synergistic effects on VSMC migration and (2) PKC, ROS, and mitogen-activated protein kinase are critical signaling molecules. OA at 100 mol/L increases VSMC migration 60Ϯ10% over control (PϽ0.001). Ang II (10 Ϫ9 mol/L) increases VSMC migration by 62Ϯ13% and 73% over control, respectively (PϽ0.01). Coincubation of cells with OA and Ang II produces a nearly additive increase in VSMC cell migration at 107Ϯ20% (PϽ0.01). Increases in VSMC migration induced by OA alone and combined with Ang II were reduced by PKC inhibition and downregulation. VSMC migration in response to OA alone and with Ang II was also inhibited by N-acetyl-cysteine, MEK inhibition, and ERK antisense. VSMC migration in response to OA alone or combined with Ang II is dependent on activation of PKC, ROS, and ERK activation, further raising the possibility that increased plasma nonesterified fatty acids and an activated renin-angiotensin-aldosterone system in subjects with the risk factor cluster contribute to accelerated atherosclerosis through a PKC, ROS, and ERK-dependent signaling pathway.

Diallyl Sulfides (DAS) and Diallyl Disulfides (DADS) Exhibit a Suppressive Effect on the Proliferation and Migration of Vascular Smooth Muscle

“…OA is a principal fatty acid in triglycerides and has its highest concentration in plasma. Several reports demonstrate that OA may induce proliferation and migration of SMC via sequential signaling pathways, including activation of PKC, ERK and PI3K, and generation of reactive oxygen species (13)(14)(15). In our present study, VSMC proliferation was induced by the stimulation of OA at concentrations of 10 to 150 µM.…”

Non-esterified fatty acids and blood pressure elevation: a mechanism for hypertension in subjects with obesity/insulin resistance?

“…53,54 In vitro studies have reported that unsaturated NEFAs, including oleic and linoleic acid, can directly activate the typical and atypical isoforms of protein kinase C (PKC) in various cell types, including VSMCs. [55][56][57][58] Among other deleterious effects on human vasculature, PKC has been shown to play a central role in mitogenic processes in VSMCs. 59,60 Several studies have clearly shown that NEFAs induce proliferation of VSMCs via PKC activation, [55][56][57] implicating a potential involvement of plasma NEFA elevation in vascular remodelling and hypertension in obese subjects.…”

“…[55][56][57][58] Among other deleterious effects on human vasculature, PKC has been shown to play a central role in mitogenic processes in VSMCs. 59,60 Several studies have clearly shown that NEFAs induce proliferation of VSMCs via PKC activation, [55][56][57] implicating a potential involvement of plasma NEFA elevation in vascular remodelling and hypertension in obese subjects. In addition, oleic and linoleic acid were reported to increase the trophic action on VSMC of other growth factors, for example insulin-like growth factor-1 (IGF-1).…”

“…In some of the above-mentioned studies, oleic acid did not only induce VSMC proliferation, but also stimulated the mitogenic response of these cells in angiotensin II, findings supporting a synergistic effect of NEFAs and angiotensin II on vascular growth. 56,57 NEFAs were also reported to activate the expression of angiotensinogen gene in preadipocytes, 63 an action possibly contributing in the upregulation of adipose tissue RAAS in subjects with central obesity. Further, an oxidized derivative of linoleic acid was recently reported to stimulate aldosterone production from rat adrenal cells, providing an alternative explanation for unexpectedly elevated aldosterone levels in some obese subjects.…”

Molecular and Cellular Mechanisms by Which Diabetes Mellitus Promotes the Development of Atherosclerosis

“…PKC inhibition blocks endothelial expression and activity of a number of adhesion molecules, including ICAM-1, P-, and E-selectins, under conditions of elevated glucose concentration [81]. AngII-and oxLDLinduced VSMC proliferation is dependent upon PKC activity [82,83]. PKC may also be involved in foam cell formation through its involvement in the induction of receptors for oxidized LDL macrophages [84].…”