Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Abstract

BackgroundPharmaceutical interventions for diabetes aim to control glycaemia and to prevent the development of complications, such as cardiovascular diseases. Some anti-hyperglycaemic drugs have been found to have adverse cardiovascular effects in their own right, limiting their therapeutic role. Glucokinase activity in the pancreas is critical in enhancing insulin release in response to hyperglycaemia. Glucokinase activators (GKAs) are novel agents for diabetes which act by enhancing the formation of glucose-6-phosphate leading to increased insulin production and subsequent suppression of blood glucose. Little, however, is known about the direct effects of GKAs on cardiovascular cells.MethodsThe effect of the GKAs RO28-1675 and Compound A on glucose utilisation in bovine aortic endothelial cells (BAEC) and rat MIN6 was observed by culturing the cells at high and low glucose concentration in the presence and absence of the GKAs and measuring glucose consumption. The effect of RO28-1675 at various concentrations on glucose-dependent signalling in BAEC was observed by measuring Smad2 phosphorylation by Western blotting. The effect of RO28-1675 on TGF-β stimulated proteoglycan synthesis was measured by 35S-SO4 incorporation and assessment of proteoglycan size by SDS-PAGE. The effects of RO28-1675 on TGF-β mediated Smad2C phosphorylation in BAEC was observed by measurement of pSmad2C levels. The direct actions of RO28-1675 on vascular reactivity were observed by measuring arteriole tone and lumen diameter.ResultsGKAs were demonstrated to increase glucose utilisation in pancreatic but not endothelial cells. Glucose-activated Smad2 phosphorylation was decreased in a dose-dependent fashion in the presence of RO28-1675. No effect of RO28-1675 was observed on TGF-β stimulated proteoglycan production. RO28-1675 caused a modest dilation in arteriole but not contractile sensitivity.ConclusionsGKA RO28-1675 did not increase glucose consumption in endothelial cells indicating the absence of glucokinase in those cells. No direct deleterious actions, in terms of atherogenic changes or excessive vasoactive effects were seen on cells or vessels of the cardiovascular system in response to GKAs. If reflected in vivo, these drugs are unlikely to have their use compromised by direct cardiovascular toxicity.

Potential Role of Dipeptidyl Peptidase IV in the Pathophysiology of Heart Failure

“…HF is characterized by cardiac dysfunction, increased renal vascular resistance and sodium retention. The findings that DPPIV catalytic activity, as well as its binding properties, are associated with increased sodium reabsorption [ 26 , 39 , 40 ], inflammation [ 41 , 42 , 43 ] and cardiac fibrosis [ 32 , 33 , 36 , 37 , 38 ] are consistent with the hypothesis that increased DPPIV activity plays a role in the pathophysiology of HF. In this review, we discuss how DPPIV might be involved in the cardio-renal axis of HF.…”

“…In addition, most peptides inactivated by DPPIV display beneficial cardiorenal functions, suggesting that inhibition of DPPIV may attenuate the development and/or progression of HF by mechanisms independent of glucose reduction. Accordingly, a large body of experimental data [ 32 , 33 , 34 , 38 , 87 , 138 ] has demonstrated that genetic deletion or pharmacological inhibition of DPPIV improves cardiovascular outcomes.…”

“…Likewise, treatment with sitagliptin improved survival post-MI in diabetic mice, and acute DPPIV inhibition was also capable of improving recovery from heart ischemia/reperfusion injury in normoglycemic mice. Additionally, four-week treatment with vildagliptin improved cardiac dysfunction, decreased fibrosis, attenuated cardiac levels of apoptosis and increased the survival rate in pressure-overloaded nondiabetic mice and rats [ 32 , 38 ]. Similarly, six-week treatment with sitagliptin significantly attenuated cardiac dysfunction in normoglycemic rats subjected to myocardial injury by radiofrequency ablation [ 33 ].…”

“…In fact, together with seprase, DPPIV forms a protease complex that contributes to cell migration and repair of connective tissue [ 31 ]. Interestingly, DPPIV inhibition has been shown to attenuate cardiac fibrosis in HF rats [ 32 , 33 , 34 ] as well as in other models of cardiac disease [ 35 , 36 , 37 , 38 ]. It is therefore tempting to speculate that an association of DPPIV with collagen and/or fibronectin may be involved in cardiac tissue remodeling, but this assumption requires further investigation.…”

<p>High-fat diet-induced kidney alterations in rats with metabolic syndrome: endothelial dysfunction and decreased antioxidant defense</p>

“…It is believed that in atherosclerosis the lack of NO bioavailability triggers smooth muscle cell constriction leading to vasospasm in nonobstructive coronary arteries, which leads to myocardial infarction. [33][34][35] Classically, neutrophils and monocytes infiltrations, proinflammatory mediators as well as elevated oxidative stress are implicated the physiopathology of vascular damage, 36 nonetheless, these cascades are still not proven participants of the paradoxical vasoconstriction phenomenon.…”