Bradykinin as a Major Endogenous Regulator of Endothelial Function

Abstract

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). Our data point to endothelial bradykinin (Bk) as a trigger for protective endothelial mechanisms. In cultured endothelial cells (CEC) Bk through kinin B2 receptors raised in a concentration-dependent manner (1pM-10 nM) free cytoplasmic calcium ions [Ca2+]i. This rise was accompanied by the release of NO as quantified by a porphyrinic sensor. Other endothelial agonists were weaker-stimulators of [Ca2+]i than Bk. In vivo we analyed the effects of exogenous Bk and of amplifiers of endogenous Bk, such as perindopril and quinapril ("tissue type" angiotensin converting enzyme inhibitors, ACE-I) on endothelial function using our original thrombolytic bioassay and EIA assays for 6-keto-PGF1alpha and t-PA antigen. A major difference found between exogenuous Bk and endogenous Bk (that rendered by "tissue ACE-I") was a) prolonged thrombolytic action (> 4h) of quinapril or perindopril. Moreover, only exogenous Bk evoked an immediate and profound hypotensive action. In vivo, Bk-induced thrombolysis was B2 kinin receptor-dependent, PGI2-mediated. The unexpected action of Bk came to light in CEC. Then appeared incubated for 4 h increased expression of mRNAs for haemoxygenase (HO-1), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGE-S), but hardly for nitric oxide synthase 2(NOS-2). We hypothesize that a network of interactions of Bk-induced enzymes may constitute a delayed phase of Bk effects in the endothelium, whereas the primary phase would be activation by BK of [Ca2+]i-dependent constitutive endothelial enzymes. In blood-perfused rat endotoxemic lungs, NO is the most eminent cytoprotective mediator. Summing up, in peripheral circulation endogenous Bk is the most efficient activator of protective endothelial function. Thrombolytic action of "tissue-type" ACE-Is relies on receptor B-2-mediated, [Ca2+]i-dependent release of PGI2. Bk also may act as a "microcytokine" by inducing mRNAs for HO-1, COX-2, or PGE-S. Activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS. This network of interactions triggered by Bk call for further studies.

The Role of Inflammation and COX-Derived Prostanoids in the Effects of Bradykinin on Isolated Rat Aorta and Urinary Bladder

“…Additionally, BK may also act as a "microcytokine" by inducing mRNAs for hemoxygenase-1 (HO-1), COX-2, or PGE synthase. The activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS [37]. We observed significant decreases in the levels of NOS when COX-3 and COX-1 were expected to be inhibited by dipyrone at 100 and 700 μM concentrations, respectively.…”

Downregulation of Bradykinin Type 2 Receptor Expression in Cardiac Endothelial Cells during Senescence

“…In previous studies, BK-2Rs have been regarded as cardioprotective [25,26] since their second messengers, e.g. nitric oxide [9,27,28], prostacyclin [29], and endothelium-derived hyperpolarizing factor [30,31] tend to support vital heart functions, and loss of BK-2Rs has since been linked to several cardiovascular disorders. The present results show that, in parallel to downregulation of BK-2Rs, mtDNA accumulates in a process that has been linked to mitochondrial malfunction [32] and to increased oxidative stress [20,33,34,35].…”

“…Since the BK-2R agonist, bradykinin, is a major regulator of endothelial cell function [9] and has been shown to prevent premature senescence of endothelial cells [10], downregulation of BK-2R may predispose to accelerated endothelial cell senescence. Similarly, cross-breeding of BK-2R knockout mice with Akita diabetes mice has led to significantly enhanced senescence in the cross-breeds, possibly as a result of increased oxidative stress [11].…”

Vascular Tone Regulation Induced by C-Type Natriuretic Peptide: Differences in Endothelium-Dependent and -Independent Mechanisms Involved in Normotensive and Spontaneously Hypertensive Rats

“…BK is one of the most potent stimulators of NO and PGI 2 release by endothelial cells [19,20]. In SHR, enhanced BK degradation may contribute to the endothelial dysfunction observed in these animals [21], even though young hypertensive rats seem not to present lower levels of BK in tissues and, on the contrary, present elevated levels of BK, as well as BK metabolites, as observed by Campbell and coworkers [22].…”