Diabetes-Induced Vascular Hypertrophy Is Accompanied by Activation of Na ⁺ -H ⁺ Exchange and Prevented by Na ⁺ -H ⁺ Exchange Inhibition

Abstract

Abstract-Vascular disease often involves vessel hypertrophy with underlying cellular hypertrophy or hyperplasia.Experimental diabetes stimulates hypertrophy of the rat mesenteric vasculature, and we investigated the hypothesis that this hypertrophy is associated with activation of Na ϩ -H ϩ exchange (NHE) activity. We measured the NHE activity in isolated, intact blood vessels from control and streptozotocin-induced diabetic adult rats using concurrent myography and fluorescence spectroscopy. The role of inhibiting NHE activity in preventing the development of the mesenteric hypertrophy in streptozotocin-diabetic rats was investigated by administration of cariporide (100 mg/kg body weight per day in 3 doses by gavage) after induction of diabetes and subsequently determining vessel weight and structure. The weight of the mesenteric vasculature was not increased 1 week after streptozotocin treatment but was significantly increased by an average of 56% at 3 weeks. NHE activity in mesenteric arteries showed an enhanced maximal velocity (V max ) in diabetic vessels at 1 and 3 weeks (0.246Ϯ0.006 and 0.238Ϯ0.007 versus 0.198Ϯ0.007 pH U/min) with no change in the apparent K m . Moreover, NHE-1 mRNA in mesenteric arterioles at 3 weeks after streptozotocin treatment was increased by Ͼ60% (55.8Ϯ6.4 versus 91.3Ϯ12.3 fg). Administration of cariporide significantly reduced mesenteric vascular weight, the wall/lumen ratio, and mesenteric extracellular matrix accumulation in the diabetic animals. Our study shows that diabetes in vivo correlates with elevated NHE activity and mRNA in the mesenteric vasculature and furthermore that inhibition of this system prevents the hypertrophic response. These data suggest that NHE may be a target for therapeutic modulation of vascular changes in diabetes.

The Amino-terminal Domains of the Ezrin, Radixin, and Moesin (ERM) Proteins Bind Advanced Glycation End Products, an Interaction That May Play a Role in the Development of Diabetic Complications

“…We have reported previously that inhibitors of AGE formation as well as cariporide (an inhibitor of a sodium/ hydrogen exchanger) can attenuate the development of diabetic complications in a rat model (55). It remains to be determined if this relates to a central role of ERM proteins that not only bind AGEs but also NHERF 1 and 2 (56) and, thus, modulate sodium/hydrogen exchangers.…”

The vasorelaxant effect of hydrogen sulfide is enhanced in streptozotocin-induced diabetic rats

“…Thus, altered tissue acidification in diabetes may contribute to the enhanced vasorelaxant effect of H 2 S. It has been demonstrated that elevated extracellular glucose concentrations regulates the Na + /H + exchanger activity in vascular smooth muscle cells (Williams and Howard 1994). Furthermore, increased activity of Na + /H + exchanger have been proposed for the altered regulation of intracellular pH in mesenteric vasculature in diabetes (Jandeleit-Dahm et al 2000). Therefore, altered intracellular pH of vascular smooth muscle cells in diabetes may cause the enhanced vasorelaxant effect of H 2 S in diabetic arteries.…”

Identification of Sites in the Second Exomembrane Loop and Ninth Transmembrane Helix of the Mammalian Na+/H+ Exchanger Important for Drug Recognition and Cation Translocation

“…HOE694, HOE642 or cariporide, and EMD85131) have been developed that inhibit the NHE isoforms with a similar rank order but over a larger concentration range (3-4 orders of magnitude) (15)(16)(17)(18). The more selective binding properties of these compounds for NHE1 have been exploited therapeutically as effective agents in the treatment of cardiac ischemia and reperfusion injuries (17)(18)(19)(20)(21)(22) and may prove beneficial in the prevention of diabetes-induced vascular hypertrophy (23). More recently, a preferential antagonist (S3226) of NHE3 has been synthesized that may also facilitate functional studies of this isoform in renal and intestinal epithelia (24,25).…”