Differential regulation of inducible and endothelial nitric oxide synthase by kinin B1 and B2 receptors

Abstract

Kinins are vasoactive peptides that play important roles in cardiovascular homeostasis, pain and inflammation. After release from their precursor kininogens, kinins or their C-terminal des-Arg metabolites activate two distinct G protein-coupled receptors (GPCR), called B2 (B2R) or B1 (B1R). The B2R is expressed constitutively with a wide tissue distribution. In contrast, the B1R is not expressed under normal conditions but is upregulated by tissue insult or inflammatory mediators. The B2R is considered to mediate many of the acute effects of kinins while the B1R is more responsible for chronic responses in inflammation. Both receptors can couple to Gαi and Gαq families of G proteins to release mediators such as nitric oxide (NO), arachidonic acid, prostaglandins, leukotrienes and endothelium derived hyperpolarizing factor and can induce the release of other inflammatory agents. The focus of this review is on the different transduction events that take place upon B2R and B1R activation in human endothelial cells that leads to generation of NO via activation of different NOS isoforms. Importantly, B2R-mediated eNOS activation leads to a transient (~ 5 min) output of NO in control endothelial cells whereas in cytokine-treated endothelial cells, B1R activation leads to very high and prolonged (~90 min) NO production that is mediated by a novel signal transduction pathway leading to post-translational activation of iNOS.

Cross-talk between Carboxypeptidase M and the Kinin B1 Receptor Mediates a New Mode of G Protein-coupled Receptor Signaling

“…We found that B1R stimulation leads to G␣ i and ERK-mediated acute activation of inducible nitric-oxide synthase and prolonged high output NO production in human lung microvascular endothelial cells (17)(18)(19). Endotheliumspecific expression of B1Rs in transgenic rats increased hypotension and lethality in response to lipopolysaccharide (LPS) (20), whereas B1R knock-out protected mice from LPS-induced hypotension, reduced neuropathic pain, and pain in response to thermal or chemical stimuli (14).…”

“…B1Rs play important roles in the endothelium, for example by promoting angiogenesis (22) and stimulating nitric oxide production (17)(18)(19)64). Endothelial B1Rs can also have deleterious effects as shown by increased hypotension and lethality in response to lipopolysaccharide administration in transgenic rats with endothelium-specific overexpression of B1Rs (20).…”

Endothelial Nitric-oxide Synthase Activation Generates an Inducible Nitric-oxide Synthase-like Output of Nitric Oxide in Inflamed Endothelium

“…This view arose from work done in rodent cells, where iNOS expression can be induced to high levels and from the fact that iNOS has basal activity that is not dependent on increased [Ca 2ϩ ] i (3,19,56). Our study challenges this notion, as we find that eNOS can generate high output NO in human endothelium under inflammatory conditions.…”

“…iNOS is considered to be the primary source of "high output" NO in inflammation (3,19,56). This view arose from work done in rodent cells, where iNOS expression can be induced to high levels and from the fact that iNOS has basal activity that is not dependent on increased [Ca 2ϩ ] i (3,19,56).…”

“…The B2R is selectively activated by bradykinin (BK) or kallidin (KD), which can be further processed by plasma carboxypeptidase N or membrane carboxypeptidase M to generate des-Arg 9 -BK or des-Arg 10 -KD, which no longer activate the B2R, but instead are specific B1R agonists (16 -18). Stimulation of the B2R or B1R differentially activates eNOS or iNOS, respectively (19). In healthy endothelium, the kinin B2R activates eNOS resulting in a short burst of Ca 2ϩ -dependent NO production (20,21).…”