title: Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice.
abstract: Diabetes is associated with a number of co-morbidities including an increased risk of developing cardiovascular diseases. The activation of Ca2+-activated proteases of the calpain family has been implicated in platelet activation associated with diabetes and this study aimed to determine the role of calpain activation in the development of endothelial dysfunction. Diabetes induction in mice attenuated acetylcholine-induced relaxation of mesenteric artery rings, an effect prevented in mice receiving a calpain inhibitor. A nitric oxide-independent but diclofenac-sensitive component of the relaxation-response was altered and correlated with a loss of prostacyclin (PGI2) generation and reduced vascular levels of PGI2synthase. Calpain inhibition was also able to restore PGI2synthase levels and PGI2generation in arteries from diabetic animals. The effects of diabetes were reproduced in vitro by a combination of high glucose and palmitate, which elicited calpain activation, PGI2synthase cleavage and inactivation as well as endothelial dysfunction in mesenteric arteries from wild-type mice. PGI2cleavage was not observed in arteries from calpain 1-/-mice or mice overexpressing the endogenous calpain inhibitor calpastatin. Finally, proteomic analyses revealed that calpain 1 cleaved the C-terminal domain of PGI2synthase close to the catalytic site of the enzyme. These data demonstrate that diabetes leads to the activation of calpain 1 in mesenteric arteries and can initiate endothelial dysfunction by cleaving and inactivating the PGI2synthase. Given that calpain inhibition prevented diabetes-induced endothelial dysfunction in mesenteric arteries, calpains represent an interesting therapeutic target for the prevention of cardiovascular complication of diabetes.
authors.affiliation: Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany. voahangy@vrc.uni-frankfurt.de.|German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt Am Main, Germany. voahangy@vrc.uni-frankfurt.de.
authors.forename: Voahanginirina
authors.identifier: 0000-0002-3542-6672
authors.initials: V
authors.lastname: Randriamboavonjy
authors.affiliation: Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany.|German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt Am Main, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kyselova
authors.affiliation: Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany.|German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt Am Main, Germany.
authors.forename: Amro
authors.initials: A
authors.lastname: Elgheznawy
authors.affiliation: German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt Am Main, Germany.|ECCPS Metabolomics Facility, Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Frankfurt Am Main, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Zukunft
authors.affiliation: Functional Proteomics, SFB 815 Core Unit, Faculty of Medicine, Goethe University, Frankfurt Am Main, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Centre for Molecular Medicine, Institute for Vascular Signalling, Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany.|German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Frankfurt Am Main, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D000818:Animals; D002154:Calpain / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D053719:Tandem Mass Spectrometry
chemical_list: D003577:Cytochrome P-450 Enzyme System; D002154:Calpain; C112682:Capn1 protein, mouse; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase
keywords: Calpain inhibitor; Diabetes mellitus; Endothelial dysfunction; Palmitate; Thromboxane A2