Evidence Linking Fatty Fat Acids, the Risk Factor Cluster, and Vascular Pathophysiology

Egan, Brent M.; Stepniakowski, K

doi:10.1007/978-1-4612-0231-8_12

Cited by 6 publications

(5 citation statements)

References 73 publications

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“…Activation of PKC is involved in regulation of vascular tone [55] and vascular smooth muscle cell growth [56] and may contribute to impaired endothelial function [57], decreased microvessel formation [58], and metabolic aspects of the risk factor cluster [59]. The isoform of PKC, which is nutritionally regulated [60], elevated in insulinresistant patients with diabetes mellitus independently of hyperglycemia [61], activated by cis-unsaturated NEFAs including oleic acid [62], and linked to mitogenic responses [63,64], may contribute to the risk factor cluster and its complications [12,13].…”

Section: Fatty Acids and Cell Signalingmentioning

confidence: 99%

“…Since NEFAs can contribute to multiple features of the cluster, these lipids may play a pathogenetic role in the insulin resistance syndrome and its complications [12,13]. NEFAs may promote metabolic features of the risk factor cluster by reducing hepatic insulin uptake, which contributes to the increased posthepatic insulin delivery and enhanced hepatic glucose output [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Nonesterified fatty acids in blood pressure control and cardiovascular complications

Egan

Greene²,

Goodfriend³

2001

Current Science Inc

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The fact that cardiovascular risk factors cluster among individuals with the insulin resistance syndrome strongly suggests a common pathogenetic denominator. For many years, abnormalities of nonesterified fatty acid metabolism have been implicated in the disturbances of carbohydrate and lipid metabolism that characterize the cluster. However, until more recently, evidence implicating fatty acids in the hemodynamic and vascular abnormalities that affect patients with this syndrome was lacking. Observations from epidemiological, clinical, and basic science suggest that fatty acids can raise blood pressure and contribute to the development of hypertension. The effects of fatty acids on blood pressure may be mediated in part by inhibition of endothelial nitric oxide synthase activity and endothelium-dependent vasodilation. Fatty acids can also increase alpha1-adrenoceptor-mediated vascular reactivity and induce vascular smooth muscle migration and proliferation. The adverse effects of fatty acids appear to be mediated in part through induction of oxidative stress. Fatty acids interact with other components of the risk factor cluster, including increased angiotensin II, to synergistically augment oxidative stress in cultured vascular smooth muscle cells. Oxidative stress is implicated in the pathogenesis of insulin resistance, hypertension, vascular remodeling, and vascular complications. A clearer definition of the specific reactive oxygen signaling pathways involved and interventions aimed at altering these pathways could lead to more rationale antioxidant therapy and improved outcomes.

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Section: Fatty Acids and Cell Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nonesterified fatty acids in blood pressure control and cardiovascular complications

Egan

Greene²,

Goodfriend³

2001

Current Science Inc

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“…[1][2][3][4] Although abdominal obesity and insulin resistance are known independent risk factors for atherosclerosis, the intermediary mechanisms are not well defined. Obese hypertensives have elevated plasma nonesterified fatty acids, including oleic acid, 5 which are highly resistant to suppression by insulin.…”

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confidence: 99%

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

et al. 2001

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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.

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“…[1][2][3][4] While abdominal obesity and insulin resistance emerge as independent risk factors for atherosclerotic disease, the intermediary mechanisms are not well defined. Evidence suggests that resistance to the fatty acid-lowering actions of insulin among insulin-resistant individuals may contribute to structural and functional vascular changes.…”

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confidence: 99%

Reactive Oxygen Species Are Critical in the Oleic Acid–Mediated Mitogenic Signaling Pathway in Vascular Smooth Muscle Cells

et al. 1998

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Abstract-Obese hypertensive patients with cardiovascular risk factor clustering have increased plasma nonesterified fatty acid levels and are at high risk for atherosclerotic events. Our previous studies demonstrated that oleic acid induces a mitogenic response in rat aortic smooth muscle cells (RASMCs) through protein kinase C (PKC)-and extracellular signal-regulated kinase (ERK)-dependent pathways. In the present study we investigated the possibility that the generation of reactive oxygen species (ROS) constitutes a critical component of the oleic acid-induced mitogenic signaling pathway in RASMCs. We studied the effect(s) of oleic acid on the generation of ROS using the oxidant-sensitive fluoroprobe 2Ј,7Ј-dichlorofluorescin diacetate. Relative fluorescence intensity and fluorescent images were obtained with laser confocal scanning microscopy from 1 to 5 minutes, since preliminary studies demonstrated that the peak fluorescence intensity occurred within 5 minutes. Oleic acid (100 mol/L) induced a time-dependent increase of cell fluorescence that was Ͼ8-fold of that seen in control cells at 5 minutes. This was blocked by catalase, which suggests that H 2 O 2 was the principal ROS. The oleic acid-induced increases in H 2 O 2 were blocked when PKC was inhibited with the use of bisindolylmaleimide and when PKC activity was downregulated by exposing RASMCs to phorbol 12-myristate 13-acetate for 24 hours. Stearic and elaidic acids, which are weak PKC activators, did not significantly increase H 2 O 2 production. The increase of H 2 O 2 in response to oleic acid was inhibited by the antioxidant N-acetylcysteine. N-Acetylcysteine also completely blocked ERK activation and the increase of thymidine incorporation in response to oleic acid. The data suggest that generation of H 2 O 2 in RASMCs exposed to oleic acid is PKC dependent. Moreover, H 2 O 2 production emerges as a critical intermediary event in the oleic acid-mediated mitogenic signaling pathway between the activation of PKC and ERK. These observations raise the possibility that the elevated plasma nonesterified fatty acids, including oleic acid, in obese hypertensive patients contribute to vascular growth and remodeling by a PKC-dependent mechanism to generate ROS that subsequently activate ERK. (Hypertension. 1998;32:1003-1010.)Key Words: muscle, smooth, vascular Ⅲ oleic acid Ⅲ kinase Ⅲ reactive oxygen species Ⅲ hydrogen peroxide O bese hypertensive patients have insulin resistance and the associated cardiovascular risk factor cluster.

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Evidence Linking Fatty Fat Acids, the Risk Factor Cluster, and Vascular Pathophysiology

Cited by 6 publications

References 73 publications

Nonesterified fatty acids in blood pressure control and cardiovascular complications

Nonesterified fatty acids in blood pressure control and cardiovascular complications

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

Reactive Oxygen Species Are Critical in the Oleic Acid–Mediated Mitogenic Signaling Pathway in Vascular Smooth Muscle Cells

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