Pathogenesis and pathophysiology of accelerated atherosclerosis in the diabetic heart.

It has been established that atherosclerotic coronary artery disease is more frequent and more severe in diabetic compared to non-diabetic subjects, but the reason for the excess risk of developing coronary macroangiopathy in diabetes remains incompletely characterized. Various biochemical mechanisms speculated to being at the "heart" of diabetic cardiac and coronary macroangiopathy are reviewed in the present article. In doing so, this article presents evidence that the labyrinthine interactions of hyperglycemia, insulin resistance, and dyslipidemia in diabetes result in a pro-atherogenic phenotype. Furthermore, the diabetic milieu yields a complex (dys)metabolic environment characterized by chronic inflammation, procoagulability, impaired fibrinolysis, neovascularization abnormalities, and microvascular defects that cumulatively alter blood rheology, artery structure, and homeostasis of the endothelium. The contributory influences of these factors in the pathophysiology of coronary artery disease in diabetes are also discussed.

Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture.

Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased MHC Ibeta mRNA levels and significantly increased MHC IIX, MHC IIB, embryonal MHC and perinatal MHC mRNA levels when compared to control. In addition, U0126 treatment significantly increased lactate dehydrogenase, creatine kinase, hexokinase, malate dehydrogenase and beta-hydroxyacyl-CoA dehydrogenase activities above control values while a significant reduction in the percentage of pyruvate dehydrogenase in the active form was also observed. Calcineurin blockade significantly decreased both MHC Ibeta and embryonal mRNA levels below control and significantly increased MHC IIX mRNA levels. Significant increases in the activities of both lactate dehydrogenase and creatine kinase above control values were also seen following cyclosporin A treatment. In conclusion, the results suggest that calcineurin upregulates slow-fibre genes and suppresses fast-fibre genes. Similarly, the ERK1/2 pathway upregulates slow-fibre MHC and suppresses fast-fibre MHC isoforms. However, the effect on enzyme activities is not fibre-type specific. The effect of U0126 on the percentage of pyruvate dehydrogenase in the active form suggests that the ERK1/2 pathway may also be involved in regulation of the phosphorylation state of this enzyme.

Exercise-induced signal transduction and gene regulation in skeletal muscle.

Skeletal muscle adapts to various forms of exercise depending on the force, speed and duration characteristics of the contraction pattern. The stresses and signals associated with each contraction pattern are likely to specifically activate a network of signal transduction pathways that integrate this information. These pathways include the calcineurin, Calcium/calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), nuclear factor kappa B (NF-κB), AMP-dependent protein kinase (AMPK), insulin signalling and developmental pathways. Activated signal transduction pathways activate or increase the expression of transcription factors via various mechanisms. Skeletal muscle genes are usually regulated by combinatorial control exerted by several transcription factors and possibly other mechanisms. In addition, adaptations such as an increase in mitochondrial biogenesis or the activation of satellite cell proliferation involve distinct regulatory mechanisms.