The Association between Angiotensin II-Induced Free Radical Generation and Membrane Fluidity in Neutrophils of Patients with Metabolic Syndrome

Abstract

Angiotensin II (Ang II) is able to induce free radical generation in neutrophils, which is more elevated in neutrophils of patients with hypercholesterolemia (HC). In addition, the signal processing through angiotensin I (Ang I) receptors is altered. In present study, we compared the Ang II-triggered free radical generation of neutrophils obtained from patients with relatively isolated forms of metabolic syndrome (MS) with membrane-bound cholesterol content and membrane fluidity. We determined the enhancement of Ang II-induced superoxide anion and leukotriene C(4) (LTC(4)) generation, membrane fluidity and cell-bound cholesterol content of neutrophils obtained from 12 control subjects, 11 patients with obesity (Ob), 10 patients with type 2 diabetes mellitus (t2-DM) and 12 patients with HC. The alteration of signal processing was studied after preincubation with different inhibiting drugs. Superoxide anion, LTC(4) production and membrane rigidity were increased in the following order: control < Ob < t2-DM < HC. Both Ang II-induced superoxide anion and LTC(4) generation were decreased in control cells by pertussis toxin and fluvastatin (Flu), whereas in each patient group, mepacrin, verapamil and Flu were effective, suggesting alterations in signal pathways, which may be attributed to isoprenylation. The enhancement of superoxide anion and LTC(4) generation correlated significantly with membrane rigidity, independently from the experimental groups and membrane-bound cholesterol content. Membrane rigidity of neutrophils, obtained from patients with MS, plays a role in Ang II-induced free radical generation independent of intracellular cholesterol homeostasis.

A Type 1 Cholecystokinin Receptor Mutant That Mimics the Dysfunction Observed for Wild Type Receptor in a High Cholesterol Environment

“…Mechanistic studies have localized the cause of the reduced coupling efficiency between CCK1R and its heterotrimeric G protein (G q ) to increased cholesterol composition of the membrane (20,21). Consistent with this, patients with pigment gallstones who are known to have normal rather than increased mem-brane cholesterol, such as is present in patients with cholesterol gallstones (22), have normal CCK1R function (19,23).…”

Intraplaque haemorrhages as the trigger of plaque vulnerability

“…94 Similar results were reported for cholesterol density in neutrophil membranes and for neutrophil sensitivity to angiotensin II-induced free radical release. 95 In contrast, circulating HDLs could have beneficial effects via their capacity to convey α1-antitrypsin 96 into the diseased tissue, whereas tobacco consumption has an inverse impact.…”

Obesity abrogates the concentration-dependent effect of leptin on endogenous cholesterol synthesis in human monocytes

“…The sensitivity of NFB to HMG CoA reductase inhibiting statins and the NFB expression increasing effect of the low cellular cholesterol level suggest a strong relationship between NFB and cholesterol synthesis (Inoue et al 2002;Guijarro et al 1996). The different degree of downregulation of PI3K in control and OW monocytes after high leptin concentration treatment most likely due to the altered membrane composition, membrane rigidity and the cholesterol accumulation in membrane rafts of OW monocytes could also play a role in the observed differences (Calleros et al 2006;Seres et al 2006).…”

“…The aim of our present study was to elucidate the effects of leptin on monocytes of OW patients, which we earlier described to possess altered membrane composition (Seres et al 2006), and to determine whether the biphasic effect of leptin on the endogenous cholesterol synthesis also occurs in OW monocytes. Moreover we tried to clarify the intracellular signal pathways of low and high leptin concentration in control and OW human monocytes undergoing high and low concentration leptin treatment.…”