Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Measurement of Body Weight and Food Intake
2.3. Measurement of Metabolites
2.4. Western Blotting Analysis
2.5. Hematoxylin and Eosin Staining
2.6. Metabolic Chamber Experiments
2.7. Exercise Capacity with a Treadmill Test
2.8. Isometric Tension Measurement with an Organ Chamber
2.9. Statistical Analysis
3. Results
3.1. Decreased SERCA2 Expression in the Aorta of db/db Mice
3.2. Decreased Body Weight and Ameliorated OGTT with CDN1163 in db/db Mice
3.3. Amelioration of Hepatosteatosis with CDN1163
3.4. Increased VO2 during Non-Exercise Load and VO2mVT with CDN1163 in the Treadmill Test of db/db Mice
3.5. Restored Endothelium-Dependent Relaxation of Aortic Rings from db/db mice with CDN1163
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- International Diabetes Federation. IDF Diabetes Atlas-8th Edition. Available online: http://www.diabetesatlas.org/ (accessed on 15 August 2018).
- Pandey, A.; Chawla, S.; Guchhait, P. Type-2 diabetes: Current understanding and future perspectives. IUBMB Life 2015, 67, 506–513. [Google Scholar] [CrossRef] [PubMed]
- Natarajan, R.; Nadler, J.L. Lipid inflammatory mediators in diabetic vascular disease. Arter. Thromb Vasc. Biol. 2004, 24, 1542–1548. [Google Scholar] [CrossRef] [PubMed]
- The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 1993, 329, 977–986. [Google Scholar] [CrossRef] [PubMed]
- UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998, 352, 837–853. [Google Scholar] [CrossRef]
- White, W.B.; Cannon, C.P.; Heller, S.R.; Nissen, S.E.; Bergenstal, R.M.; Bakris, G.L.; Perez, A.T.; Fleck, P.R.; Mehta, C.R.; Kupfer, S.; et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013, 369, 1327–1335. [Google Scholar] [CrossRef] [Green Version]
- Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef] [Green Version]
- ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 2008, 358, 2560–2572. [Google Scholar] [CrossRef] [Green Version]
- Gerstein, H.C.; Miller, M.E.; Byington, R.P.; Goff, D.C., Jr.; Bigger, J.T.; Buse, J.B.; Cushman, W.C.; Genuth, S.; Ismail-Beigi, F.; Grimm, R.H., Jr.; et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 2008, 358, 2545–2559. [Google Scholar] [CrossRef] [Green Version]
- Duckworth, W.; Abraira, C.; Moritz, T.; Reda, D.; Emanuele, N.; Reaven, P.D.; Zieve, F.J.; Marks, J.; Davis, S.N.; Hayward, R.; et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 2009, 360, 129–139. [Google Scholar] [CrossRef] [Green Version]
- Masaki, N.; Ido, Y.; Yamada, T.; Yamashita, Y.; Toya, T.; Takase, B.; Hamburg, N.M.; Adachi, T. Endothelial Insulin Resistance of Freshly Isolated Arterial Endothelial Cells From Radial Sheaths in Patients With Suspected Coronary Artery Disease. J. Am. Heart Assoc. 2019, 8, e010816. [Google Scholar] [CrossRef]
- Brini, M.; Carafoli, E. Calcium pumps in health and disease. Physiol Rev. 2009, 89, 1341–1378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, S.W.; Zhou, Y.; Lee, J.; Lee, J.; Ozcan, U. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc. Natl. Acad. Sci. USA 2010, 107, 19320–19325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guerrero-Hernandez, A.; Leon-Aparicio, D.; Chavez-Reyes, J.; Olivares-Reyes, J.A.; DeJesus, S. Endoplasmic reticulum stress in insulin resistance and diabetes. Cell Calcium 2014, 56, 311–322. [Google Scholar] [CrossRef] [PubMed]
- Zarain-Herzberg, A.; Garcia-Rivas, G.; Estrada-Aviles, R. Regulation of SERCA pumps expression in diabetes. Cell Calcium 2014, 56, 302–310. [Google Scholar] [CrossRef]
- Pereira, L.; Ruiz-Hurtado, G.; Rueda, A.; Mercadier, J.J.; Benitah, J.P.; Gomez, A.M. Calcium signaling in diabetic cardiomyocytes. Cell Calcium 2014, 56, 372–380. [Google Scholar] [CrossRef]
- Shah, M.S.; Brownlee, M. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. Circ. Res. 2016, 118, 1808–1829. [Google Scholar] [CrossRef] [Green Version]
- Adachi, T. Modulation of vascular sarco/endoplasmic reticulum calcium ATPase in cardiovascular pathophysiology. Adv. Pharm. 2010, 59, 165–195. [Google Scholar] [CrossRef]
- Adachi, T.; Matsui, R.; Weisbrod, R.M.; Najibi, S.; Cohen, R.A. Reduced sarco/endoplasmic reticulum Ca(2+) uptake activity can account for the reduced response to NO, but not sodium nitroprusside, in hypercholesterolemic rabbit aorta. Circulation 2001, 104, 1040–1045. [Google Scholar] [CrossRef] [Green Version]
- Adachi, T.; Weisbrod, R.M.; Pimentel, D.R.; Ying, J.; Sharov, V.S.; Schoneich, C.; Cohen, R.A. S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat. Med. 2004, 10, 1200–1207. [Google Scholar] [CrossRef]
- Liang, C.P.; Han, S.; Li, G.; Tabas, I.; Tall, A.R. Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment. Diabetes 2012, 61, 2609–2620. [Google Scholar] [CrossRef] [Green Version]
- Sordi, G.; Goti, A.; Young, H.S.; Palchetti, I.; Tadini-Buoninsegni, F. Stimulation of Ca(2+)-ATPase Transport Activity by a Small-Molecule Drug. ChemMedChem 2021, 16, 3293–3299. [Google Scholar] [CrossRef] [PubMed]
- Kang, S.; Dahl, R.; Hsieh, W.; Shin, A.; Zsebo, K.M.; Buettner, C.; Hajjar, R.J.; Lebeche, D. Small Molecular Allosteric Activator of the Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Attenuates Diabetes and Metabolic Disorders. J. Biol. Chem. 2016, 291, 5185–5198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- He, Q.; Pu, J.; Yuan, A.; Yao, T.; Ying, X.; Zhao, Y.; Xu, L.; Tong, H.; He, B. Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc. Diabetol. 2014, 13, 149. [Google Scholar] [CrossRef] [Green Version]
- Terauchi, Y.; Tsuji, Y.; Satoh, S.; Minoura, H.; Murakami, K.; Okuno, A.; Inukai, K.; Asano, T.; Kaburagi, Y.; Ueki, K.; et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase. Nat. Genet. 1999, 21, 230–235. [Google Scholar] [CrossRef] [PubMed]
- Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976, 72, 248–254. [Google Scholar] [CrossRef]
- Kawai, S.; Takagi, Y.; Kaneko, S.; Kurosawa, T. Effect of three types of mixed anesthetic agents alternate to ketamine in mice. Exp. Anim. 2011, 60, 481–487. [Google Scholar] [CrossRef] [Green Version]
- Choi, H.M.; Kim, H.R.; Kim, E.K.; Byun, Y.S.; Won, Y.S.; Yoon, W.K.; Kim, H.C.; Kang, J.G.; Nam, K.H. An age-dependent alteration of the respiratory exchange ratio in the db/db mouse. Lab. Anim. Res. 2015, 31, 1–6. [Google Scholar] [CrossRef] [Green Version]
- Ostler, J.E.; Maurya, S.K.; Dials, J.; Roof, S.R.; Devor, S.T.; Ziolo, M.T.; Periasamy, M. Effects of insulin resistance on skeletal muscle growth and exercise capacity in type 2 diabetic mouse models. Am. J. Physiol. Endocrinol. Metab. 2014, 306, E592–E605. [Google Scholar] [CrossRef] [Green Version]
- Kujiraoka, T.; Satoh, Y.; Ayaori, M.; Shiraishi, Y.; Arai-Nakaya, Y.; Hakuno, D.; Yada, H.; Kuwada, N.; Endo, S.; Isoda, K.; et al. Hepatic extracellular signal-regulated kinase 2 suppresses endoplasmic reticulum stress and protects from oxidative stress and endothelial dysfunction. J. Am. Heart Assoc. 2013, 2, e000361. [Google Scholar] [CrossRef] [Green Version]
- Faldt, J.; Wernstedt, I.; Fitzgerald, S.M.; Wallenius, K.; Bergstrom, G.; Jansson, J.O. Reduced exercise endurance in interleukin-6-deficient mice. Endocrinology 2004, 145, 2680–2686. [Google Scholar] [CrossRef] [Green Version]
- Cheang, W.S.; Wong, W.T.; Zhao, L.; Xu, J.; Wang, L.; Lau, C.W.; Chen, Z.Y.; Ma, R.C.; Xu, A.; Wang, N.; et al. PPARdelta Is Required for Exercise to Attenuate Endoplasmic Reticulum Stress and Endothelial Dysfunction in Diabetic Mice. Diabetes 2017, 66, 519–528. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Petersen, M.C.; Vatner, D.F.; Shulman, G.I. Regulation of hepatic glucose metabolism in health and disease. Nat. Rev. Endocrinol. 2017, 13, 572–587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Baron, A.D.; Brechtel-Hook, G.; Johnson, A.; Cronin, J.; Leaming, R.; Steinberg, H.O. Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake. Am. J. Physiol. 1996, 271, E1067–E1072. [Google Scholar] [CrossRef]
- Kubota, T.; Kubota, N.; Kumagai, H.; Yamaguchi, S.; Kozono, H.; Takahashi, T.; Inoue, M.; Itoh, S.; Takamoto, I.; Sasako, T.; et al. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011, 13, 294–307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998, 352, 854–865. [Google Scholar] [CrossRef]
- Lipskaia, L.; Hadri, L.; Lopez, J.J.; Hajjar, R.J.; Bobe, R. Benefit of SERCA2a gene transfer to vascular endothelial and smooth muscle cells: A new aspect in therapy of cardiovascular diseases. Curr. Vasc. Pharmacol. 2013, 11, 465–479. [Google Scholar] [CrossRef]
- Viner, R.I.; Ferrington, D.A.; Williams, T.D.; Bigelow, D.J.; Schoneich, C. Protein modification during biological aging: Selective tyrosine nitration of the SERCA2a isoform of the sarcoplasmic reticulum Ca2+-ATPase in skeletal muscle. Biochem. J. 1999, 340, 657–669. [Google Scholar] [CrossRef]
- Viner, R.I.; Williams, T.D.; Schoneich, C. Peroxynitrite modification of protein thiols: Oxidation, nitrosylation, and S-glutathiolation of functionally important cysteine residue(s) in the sarcoplasmic reticulum Ca-ATPase. Biochemistry 1999, 38, 12408–12415. [Google Scholar] [CrossRef]
- Boutagy, N.E.; Rogers, G.W.; Pyne, E.S.; Ali, M.M.; Hulver, M.W.; Frisard, M.I. Using Isolated Mitochondria from Minimal Quantities of Mouse Skeletal Muscle for High throughput Microplate Respiratory Measurements. J. Vis. Exp. 2015, 30, e53216. [Google Scholar] [CrossRef] [Green Version]
- Bauer, T.A.; Reusch, J.E.; Levi, M.; Regensteiner, J.G. Skeletal muscle deoxygenation after the onset of moderate exercise suggests slowed microvascular blood flow kinetics in type 2 diabetes. Diabetes Care 2007, 30, 2880–2885. [Google Scholar] [CrossRef] [Green Version]
- Mac Ananey, O.; Malone, J.; Warmington, S.; O’Shea, D.; Green, S.; Egana, M. Cardiac output is not related to the slowed O2 uptake kinetics in type 2 diabetes. Med. Sci. Sports Exerc. 2011, 43, 935–942. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mengeste, A.M.; Lund, J.; Katare, P.; Ghobadi, R.; Bakke, H.G.; Lunde, P.K.; Eide, L.; Mahony, G.O.; Gopel, S.; Peng, X.R.; et al. The small molecule SERCA activator CDN1163 increases energy metabolism in human skeletal muscle cells. Curr. Res. Pharmacol. Drug Discov. 2021, 2, 100060. [Google Scholar] [CrossRef] [PubMed]
- Qin, X.; Zheng, X.; Qi, H.; Dou, D.; Raj, J.U.; Gao, Y. cGMP-dependent protein kinase in regulation of basal tone and in nitroglycerin- and nitric-oxide-induced relaxation i.in porcine coronary artery. Pflug. Arch. 2007, 454, 913–923. [Google Scholar] [CrossRef] [PubMed]
- Ying, J.; Sharov, V.; Xu, S.; Jiang, B.; Gerrity, R.; Schöneich, C.; Cohen, R.A. Cysteine-674 Oxidation and Degradation of SERCA in Diabetic Pig Aorta. Free Radic. Biol. Med. 2008, 45, 756–762. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thompson, M.D.; Mei, Y.; Weisbrod, R.M.; Silver, M.; Shukla, P.C.; Bolotina, V.M.; Cohen, R.A.; Tong, X. Glutathione adducts on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic function as well as promote ischemic blood flow recovery. J. Biol. Chem. 2014, 289, 19907–19916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, J.A.; Montagnani, M.; Koh, K.K.; Quon, M.J. Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms. Circulation 2006, 113, 1888–1904. [Google Scholar] [CrossRef]
- Dimmeler, S.; Fleming, I.; Fisslthaler, B.; Hermann, C.; Busse, R.; Zeiher, A.M. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999, 399, 601–605. [Google Scholar] [CrossRef]
- Ozcan, U.; Cao, Q.; Yilmaz, E.; Lee, A.H.; Iwakoshi, N.N.; Ozdelen, E.; Tuncman, G.; Gorgun, C.; Glimcher, L.H.; Hotamisligil, G.S. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004, 306, 457–461. [Google Scholar] [CrossRef] [Green Version]
- Back, S.h.; Kaufman, R.J. Endoplasmic reticulum stress and type 2 diabetes. Annu. Rev. Biochem. 2012, 81, 767–793. [Google Scholar] [CrossRef] [Green Version]
- Malhi, H.; Kaufman, R.J. Endoplasmic reticulum stress in liver disease. J. Hepatol. 2011, 54, 795–809. [Google Scholar] [CrossRef] [Green Version]
- Zhang, K.; Wang, S.; Malhotra, J.; Hassler, J.R.; Back, S.H.; Wang, G.; Chang, L.; Xu, W.; Miao, H.; Leonardi, R.; et al. The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J. 2011, 30, 1357–1375. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Laybutt, D.R.; Preston, A.M.; Akerfeldt, M.C.; Kench, J.G.; Busch, A.K.; Biankin, A.V.; Biden, T.J. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 2007, 50, 752–763. [Google Scholar] [CrossRef] [PubMed]
- Rocha, M.; Diaz-Morales, N.; Rovira-Llopis, S.; Escribano-Lopez, I.; Banuls, C.; Hernandez-Mijares, A.; Diamanti-Kandarakis, E.; Victor, V.M. Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Diabetes. Curr. Pharm. Des. 2016, 22, 2640–2649. [Google Scholar] [CrossRef] [PubMed]
- Takada, A.; Miki, T.; Kuno, A.; Kouzu, H.; Sunaga, D.; Itoh, T.; Tanno, M.; Yano, T.; Sato, T.; Ishikawa, S.; et al. Role of ER stress in ventricular contractile dysfunction in type 2 diabetes. PLoS ONE 2012, 7, e39893. [Google Scholar] [CrossRef]
- Randriamboavonjy, V.; Pistrosch, F.; Bolck, B.; Schwinger, R.H.; Dixit, M.; Badenhoop, K.; Cohen, R.A.; Busse, R.; Fleming, I. Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATP.Pase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone. Circulation 2008, 117, 52–60. [Google Scholar] [CrossRef] [Green Version]
- Dahl, R. A new target for Parkinson’s disease: Small molecule SERCA activator CDN1163 ameliorates dyskinesia in 6-OHDA-lesioned rats. Bioorganic Med. Chem. 2017, 25, 53–57. [Google Scholar] [CrossRef]
- Kim, O.K.; Nam, D.E.; Jun, W.; Lee, J. Cudrania tricuspidata water extract improved obesity-induced hepatic insulin resistance in db/db mice by suppressing ER stress and inflammation. Food Nutr. Res. 2015, 59, 29165. [Google Scholar] [CrossRef] [Green Version]
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Kimura, T.; Kagami, K.; Sato, A.; Osaki, A.; Ito, K.; Horii, S.; Toya, T.; Masaki, N.; Yasuda, R.; Nagatomo, Y.; et al. Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice. Cells 2022, 11, 1488. https://doi.org/10.3390/cells11091488
Kimura T, Kagami K, Sato A, Osaki A, Ito K, Horii S, Toya T, Masaki N, Yasuda R, Nagatomo Y, et al. Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice. Cells. 2022; 11(9):1488. https://doi.org/10.3390/cells11091488
Chicago/Turabian StyleKimura, Toyokazu, Kazuki Kagami, Atsushi Sato, Ayumu Osaki, Kei Ito, Shunpei Horii, Takumi Toya, Nobuyuki Masaki, Risako Yasuda, Yuji Nagatomo, and et al. 2022. "Sarco/Endoplasmic Reticulum Ca2+ ATPase 2 Activator Ameliorates Endothelial Dysfunction; Insulin Resistance in Diabetic Mice" Cells 11, no. 9: 1488. https://doi.org/10.3390/cells11091488