Distinct and complementary roles for α and β isoenzymes of PKC in mediating vasoconstrictor responses to acutely elevated glucose

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Abstract

We investigated the hypothesis that elevated glucose increases contractile responses in vascular smooth muscle and that this enhanced constriction occurs due to the glucose-induced PKC-dependent inhibition of voltage-gated potassium channels.

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Mechanisms underlying endothelial dysfunction in diabetes mellitus.

U Hink, H. Li, H Mollnau … (2001)

Incubation of endothelial cells in vitro with high concentrations of glucose activates protein kinase C (PKC) and increases nitric oxide synthase (NOS III) gene expression as well as superoxide production. The underlying mechanisms remain unknown. To address this issue in an in vivo model, diabetes was induced with streptozotocin in rats. Streptozotocin treatment led to endothelial dysfunction and increased vascular superoxide production, as assessed by lucigenin- and coelenterazine-derived chemiluminescence. The bioavailability of vascular nitric oxide (as measured by electron spin resonance) was reduced in diabetic aortas, although expression of endothelial NOS III (mRNA and protein) was markedly increased. NOS inhibition with N:(G)-nitro-L-arginine increased superoxide levels in control vessels but reduced them in diabetic vessels, identifying NOS as a superoxide source. Similarly, we found an activation of the NADPH oxidase and a 7-fold increase in gp91(phox) mRNA in diabetic vessels. In vitro PKC inhibition with chelerythrine reduced vascular superoxide in diabetic vessels, whereas it had no effect on superoxide levels in normal vessels. In vivo PKC inhibition with N:-benzoyl-staurosporine did not affect glucose levels in diabetic rats but prevented NOS III gene upregulation and NOS-mediated superoxide production, thereby restoring vascular nitric oxide bioavailability and endothelial function. The reduction of superoxide in vitro by chelerythrine and the normalization of NOS III gene expression and reduction of superoxide in vivo by N:-benzoyl-staurosporine point to a decisive role of PKC in mediating these phenomena and suggest a therapeutic potential of PKC inhibitors in the prevention or treatment of vascular complications of diabetes mellitus. The full text of this article is available at http://www.circresaha.org.

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PKC and the control of localized signal dynamics.

Angus J M Cameron, Katrina Boeckeler, Stephanie Kermorgant … (2010)

Networks of signal transducers determine the conversion of environmental cues into cellular actions. Among the main players in these networks are protein kinases, which can acutely and reversibly modify protein functions to influence cellular events. One group of kinases, the protein kinase C (PKC) family, have been increasingly implicated in the organization of signal propagation, particularly in the spatial distribution of signals. Examples of where and how various PKC isoforms direct this tier of signal organization are becoming more evident.

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Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction.

Katsuomi Iwakura, Hiroshi Ito, Masashi Ikushima … (2003)

We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). Hyperglycemia is associated with increased risks of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography (MCE) after successful reperfusion within 24 h after symptom onset. Two-dimensional echocardiography was recorded on day 1 and three months later to determine the change in the wall motion score (DeltaWMS; sum of 16 segmental scores; dyskinesia = 4 to normokinesia = 0). The no-reflow phenomenon was found on MCE in 49 (33.6%) of 146 patients; their glucose level on hospital admission was significantly higher than that of patients who did not exhibit this phenomenon (209 +/- 79 vs. 159 +/- 56 mg/dl; p /=160 mg/dl) than in those without hyperglycemia (52.0% vs. 14.1%; p < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2,497 +/- 1,603 vs. 1,804 +/- 1,300 IU/l; p = 0.005) and a lower DeltaWMS (3.7 +/- 4.8 vs. 5.7 +/- 4.3; p = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no reflow, along with age, gender, absence of pre-infarction angina, complete occlusion of the culprit lesion, and anterior AMI. Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and worse functional recovery.