Bradykinin Inhibits Serum-Depletion-Induced Apoptosis of Human Vascular Endothelial Cells by Inducing Nitric Oxide via Calcium Ion Kinetics

Abstract

Vascular endothelial cells play important roles in atherogenesis, and bradykinin is associated with atherosclerosis. The effect of bradykinin on apoptosis in human umbilical vein endothelial cells (HUVECs) was investigated, with a focus on Ca2+ kinetics and nitric oxide production. In serum-free conditions, the number of apoptotic cells increased in a time-dependent manner, but this increase was inhibited by bradykinin in a dose-dependent manner. The apoptosis inhibited by bradykinin was reduced by nitric oxide inhibitor N(G)-monomethyl-L-arginine (L-NMMA) and consequently restored by combined treatment with L-NMMA and L-arginine. Bradykinin increased influx of extracellular Ca2+, generation of inositol 1,4,5-trisphosphate, and release of Ca2+ from intracellular storage sites, thus increasing the total intracellular Ca2+ concentration ([Ca2+]i). Bradykinin increased nitric oxide production, which was inhibited by L-NMMA and restored by combined treatment with L-NMMA and L-arginine. Sodium nitroprusside (SNP) dose-dependently increased nitric oxide production and inhibited apoptosis; however, 10(-5) M SNP did not inhibit apoptosis. Caspase-3 inhibitor, acetyl-Asp-Met-Gln-Asp-aldehyde, enhanced bradykinin-induced inhibition of apoptosis but did not effect bradykinin-induced nitric oxide production. These findings suggest that bradykinin inhibits serum-depletion-induced apoptosis in HUVECs by enhancing nitric oxide production via an increase in [Ca2+]i.

Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli

“…In addition to various other biological effects, BK has been shown to protect ECs against apoptotic cell death in vitro (Fujita et al, 2000;Gryglewski et al, 2001;Kono et al, 2002;Ceconi et al, 2007). More recently, Oeseburg et al (2009) used cultured bovine aortic EC to show that BK may also protect ECs against oxidative stress-induced senescence.…”

“…Nearly all of the in vitro functional studies that have demonstrated real EC protection against noxious stimuli by BK, either added or endogenously produced via ACEi and ARA treatments, were conducted on macrovascular ECs from conductance vessels such as the bovine aorta (Gryglewski et al, 2001), the human umbilical vein (HUVEC) (Kono et al, 2002;Ceconi et al, 2007), and the human aorta (HAEC) (Fujita et al, 2000). There is no doubt about functional phenotypic heterogeneity of ECs between macro-and microvessels.…”

ACE inhibition with perindopril and endothelial function. Results of a substudy of the EUROPA study: PERTINENT

“…To answer this question, we have measured the balance between Ang II and BK, as they are modulated by ACE and exert pro-apoptotic and anti-apoptotic effects on the endothelium, respectively [25,26]. An increase in BK levels is also expected to stimulate eNOS protein expression and activity.…”

Modulation by bradykinin and nitric oxide of angiotensin II-induced apoptosis in a vascular smooth muscle cell phenotype

“…Reports on BK as modulator of apoptosis are very few. In vitro, BK has been reported to inhibit serum-depletion-induced apoptosis of endothelial cells by increased NO production [15]. In the heart, BK is considered as a cardioprotective agent which prevents apoptosis [16] possibly via an NO pathway.…”