title: Ca2+-sensing receptor cleavage by calpain partially accounts for altered vascular reactivity in mice fed a high-fat diet.
abstract: The Ca-sensing receptor (CaSR) is expressed in endothelial and smooth muscle cells, but its role in regulating vascular reactivity is unclear, as are the effects of disease on CaSR function and expression. We studied vascular reactivity in aortic segments from healthy and diabetic mice, combined with in vitro proteolysis studies and Western blot analyses of CaSR expression in tissue samples. In endothelium-intact aortic rings, extracellular Ca elicited a nitric oxide-dependent relaxation that was attenuated by the CaSR antagonist, NPS2390. The calcimimetic, calindol, induced the endothelium-independent relaxation of aortic segments that was also sensitive to NPS2390. The antagonist failed to affect responses to acetylcholine or U46619 but attenuated contractions to phenylephrine and potassium. In mice fed a Western-type diet, phenylephrine-induced contractions and calindol-induced relaxations were markedly attenuated, and CaSR expression was decreased. The latter phenomenon could be attributed to the activation of the Ca-dependent protease, µ-calpain, and the subsequent proteolytic cleavage of the CaSR. CaSR activation in smooth muscle cells modulates vascular responsiveness to Ca-elevating agonists. These effects are blunted during metabolic stress because of the limited proteolysis of the CaSR by calpain. The loss of the CaSR function may predispose to the macrovascular late complications associated with diabetes.
authors: Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Frankfurt am Main, Germany. loot@vrc.uni-frankfurt.de
authors: Annemarieke E
authors: AE
authors: Loot
authors: Ina
authors: I
authors: Pierson
authors: Tetyana
authors: T
authors: Syzonenko
authors: Amro
authors: A
authors: Elgheznawy
authors: Voahanginirina
authors: V
authors: Randriamboavonjy
authors: Aleksandra
authors: A
authors: Zivković
authors: Holger
authors: H
authors: Stark
authors: Ingrid
authors: I
authors: Fleming
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002154:Calpain / Q000494:pharmacology*; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D059305:Diet, High-Fat; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: C569355:2-quinoxaline-carboxamide-N-adamantan-1-yl; D017931:DNA Primers; D011810:Quinoxalines; D044169:Receptors, Calcium-Sensing; D014662:Vasoconstrictor Agents; D002154:Calpain; D000218:Adamantane