nach oben

Erschienen in:

18.02.2019 | Article

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis

verfasst von: Xiaomei Teng, Chen Ji, Huiting Zhong, Dong Zheng, Rui Ni, David J. Hill, Sidong Xiong, Guo-Chang Fan, Peter A. Greer, Zhenya Shen, Tianqing Peng

Erschienen in: Diabetologia | Ausgabe 5/2019

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

The role of non-cardiomyocytes in diabetic cardiomyopathy has not been fully addressed. This study investigated whether endothelial cell calpain plays a role in myocardial endothelial injury and microvascular rarefaction in diabetes, thereby contributing to diabetic cardiomyopathy.

Methods

Endothelial cell-specific Capns1-knockout (KO) mice were generated. Conditions mimicking prediabetes and type 1 and type 2 diabetes were induced in these KO mice and their wild-type littermates. Myocardial function and coronary flow reserve were assessed by echocardiography. Histological analyses were performed to determine capillary density, cardiomyocyte size and fibrosis in the heart. Isolated aortas were assayed for neovascularisation. Cultured cardiac microvascular endothelial cells were stimulated with high palmitate. Angiogenesis and apoptosis were analysed.

Results

Endothelial cell-specific deletion of Capns1 disrupted calpain 1 and calpain 2 in endothelial cells, reduced cardiac fibrosis and hypertrophy, and alleviated myocardial dysfunction in mouse models of diabetes without significantly affecting systemic metabolic variables. These protective effects of calpain disruption in endothelial cells were associated with an increase in myocardial capillary density (wild-type vs Capns1-KO 3646.14 ± 423.51 vs 4708.7 ± 417.93 capillary number/high-power field in prediabetes, 2999.36 ± 854.77 vs 4579.22 ± 672.56 capillary number/high-power field in type 2 diabetes and 2364.87 ± 249.57 vs 3014.63 ± 215.46 capillary number/high-power field in type 1 diabetes) and coronary flow reserve. Ex vivo analysis of neovascularisation revealed more endothelial cell sprouts from aortic rings of prediabetic and diabetic Capns1-KO mice compared with their wild-type littermates. In cultured cardiac microvascular endothelial cells, inhibition of calpain improved angiogenesis and prevented apoptosis under metabolic stress. Mechanistically, deletion of Capns1 elevated the protein levels of β-catenin in endothelial cells of Capns1-KO mice and constitutive activity of calpain 2 suppressed β-catenin protein expression in cultured endothelial cells. Upregulation of β-catenin promoted angiogenesis and inhibited apoptosis whereas knockdown of β-catenin offset the protective effects of calpain inhibition in endothelial cells under metabolic stress.

Conclusions/interpretation

These results delineate a primary role of calpain in inducing cardiac endothelial cell injury and impairing neovascularisation via suppression of β-catenin, thereby promoting diabetic cardiomyopathy, and indicate that calpain is a promising therapeutic target to prevent diabetic cardiac complications.

Nur mit Berechtigung zugänglich

Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11):e442. https://doi.org/10.1371/journal.pmed.0030442 CrossRefPubMedPubMedCentral

Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr (2004) Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care 27(3):699–703. https://doi.org/10.2337/diacare.27.3.699 CrossRefPubMed

Boudina S, Abel ED (2007) Diabetic cardiomyopathy revisited. Circulation 115(25):3213–3223. https://doi.org/10.1161/CIRCULATIONAHA.106.679597 CrossRefPubMed

Goll DE, Thompson VF, Li H, Wei W, Cong J (2003) The calpain system. Physiol Rev 83(3):731–801. https://doi.org/10.1152/physrev.00029.2002 CrossRefPubMed

Fujitani K, Kambayashi J, Sakon M et al (1997) Identification of mu-, m-calpains and calpastatin and capture of mu-calpain activation in endothelial cells. J Cell Biochem 66(2):197–209. https://doi.org/10.1002/(SICI)1097-4644(19970801)66:2<197::AID-JCB7>3.0.CO;2-L CrossRefPubMed

Tan Y, Dourdin N, Wu C, De Veyra T, Elce JS, Greer PA (2006) Conditional disruption of ubiquitous calpains in the mouse. Genesis 44(6):297–303. https://doi.org/10.1002/dvg.20216 CrossRefPubMed

Li Y, Ma J, Zhu H et al (2011) Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes. Diabetes 60(11):2985–2994. https://doi.org/10.2337/db10-1333 CrossRefPubMedPubMedCentral

Li S, Zhang L, Ni R et al (2016) Disruption of calpain reduces lipotoxicity-induced cardiac injury by preventing endoplasmic reticulum stress. Biochim Biophys Acta 1862(11):2023–2033. https://doi.org/10.1016/j.bbadis.2016.08.005 CrossRefPubMedPubMedCentral

Ni R, Zheng D, Xiong S et al (2016) Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type 1 diabetic hearts: a novel mechanism contributing to diabetic cardiomyopathy. Diabetes 65:255–268PubMed

10.

Aronson D, Edelman ER (2014) Coronary artery disease and diabetes mellitus. Cardiol Clin 32(3):439–455. https://doi.org/10.1016/j.ccl.2014.04.001 CrossRefPubMedPubMedCentral

11.

Beckman JA, Paneni F, Cosentino F, Creager MA (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II. Eur Heart J 34(31):2444–2452. https://doi.org/10.1093/eurheartj/eht142 CrossRefPubMed

12.

Hinkel R, Hoewe A, Renner S et al (2017) Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol 69(2):131–143. https://doi.org/10.1016/j.jacc.2016.10.058 CrossRefPubMed

13.

Muris DM, Houben AJ, Schram MT, Stehouwer CD (2012) Microvascular dysfunction is associated with a higher incidence of type 2 diabetes mellitus: a systematic review and meta-analysis. Arterioscler Thromb Vasc Biol 32(12):3082–3094. https://doi.org/10.1161/ATVBAHA.112.300291 CrossRefPubMed

14.

Sabanayagam C, Lye WK, Klein R et al (2015) Retinal microvascular calibre and risk of diabetes mellitus: a systematic review and participant-level meta-analysis. Diabetologia 58(11):2476–2485. https://doi.org/10.1007/s00125-015-3717-2 CrossRefPubMedPubMedCentral

15.

Stalker TJ, Gong Y, Scalia R (2005) The calcium-dependent protease calpain causes endothelial dysfunction in type 2 diabetes. Diabetes 54(4):1132–1140. https://doi.org/10.2337/diabetes.54.4.1132 CrossRefPubMed

16.

Scalia R, Gong Y, Berzins B, Zhao LJ, Sharma K (2007) Hyperglycemia is a major determinant of albumin permeability in diabetic microcirculation: the role of mu-calpain. Diabetes 56(7):1842–1849. https://doi.org/10.2337/db06-1198 CrossRefPubMed

17.

Smolock AR, Mishra G, Eguchi K, Eguchi S, Scalia R (2011) Protein kinase C upregulates intercellular adhesion molecule-1 and leukocyte-endothelium interactions in hyperglycemia via activation of endothelial expressed calpain. Arterioscler Thromb Vasc Biol 31(2):289–296. https://doi.org/10.1161/ATVBAHA.110.217901 CrossRefPubMed

18.

Chen B, Zhao Q, Ni R et al (2014) Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes. Cardiovasc Diabetol 13(1):88. https://doi.org/10.1186/1475-2840-13-88 CrossRefPubMedPubMedCentral

19.

Randriamboavonjy V, Kyselova A, Elgheznawy A, Zukunft S, Wittig I, Fleming I (2017) Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. Basic Res Cardiol 112(1):10. https://doi.org/10.1007/s00395-016-0596-8 CrossRefPubMed

20.

Hinder LM, O’Brien PD, Hayes JM et al (2017) Dietary reversal of neuropathy in a murine model of prediabetes and metabolic syndrome. Dis Model Mech 10(6):717–725. https://doi.org/10.1242/dmm.028530 CrossRefPubMedPubMedCentral

21.

Kusakabe T, Tanioka H, Ebihara K et al (2009) Beneficial effects of leptin on glycaemic and lipid control in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and a high-fat diet. Diabetologia 52(4):675–683. https://doi.org/10.1007/s00125-009-1258-2 CrossRefPubMed

22.

Li Y, Li Y, Feng Q, Arnold M, Peng T (2009) Calpain activation contributes to hyperglycaemia-induced apoptosis in cardiomyocytes. Cardiovasc Res 84(1):100–110. https://doi.org/10.1093/cvr/cvp189 CrossRefPubMed

23.

Baker M, Robinson SD, Lechertier T et al (2011) Use of the mouse aortic ring assay to study angiogenesis. Nat Protoc 7(1):89–104. https://doi.org/10.1038/nprot.2011.435 CrossRefPubMed

24.

Dror E, Dalmas E, Meier DT et al (2017) Postprandial macrophage-derived IL-1beta stimulates insulin, and both synergistically promote glucose disposal and inflammation. Nat Immunol 18(3):283–292. https://doi.org/10.1038/ni.3659 CrossRefPubMed

25.

Zheng D, Ma J, Yu Y et al (2015) Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia 58(8):1949–1958. https://doi.org/10.1007/s00125-015-3622-8 CrossRefPubMedPubMedCentral

26.

Liang CC, Park AY, Guan JL (2007) In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2(2):329–333. https://doi.org/10.1038/nprot.2007.30 CrossRefPubMed

27.

Graesser D, Solowiej A, Bruckner M et al (2002) Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice. J Clin Invest 109(3):383–392. https://doi.org/10.1172/JCI0213595 CrossRefPubMedPubMedCentral

28.

Oskarsson G (2004) Coronary flow and flow reserve in children. Acta Paediatr Suppl 93:20–25CrossRef

29.

Nakagami H, Kaneda Y, Ogihara T, Morishita R (2005) Endothelial dysfunction in hyperglycemia as a trigger of atherosclerosis. Curr Diabetes Rev 1(1):59–63. https://doi.org/10.2174/1573399052952550 CrossRefPubMed

30.

Cohen G, Riahi Y, Alpert E, Gruzman A, Sasson S (2007) The roles of hyperglycaemia and oxidative stress in the rise and collapse of the natural protective mechanism against vascular endothelial cell dysfunction in diabetes. Arch Physiol Biochem 113(4-5):259–267. https://doi.org/10.1080/13813450701783513 CrossRefPubMed

31.

Heather LC, Clarke K (2011) Metabolism, hypoxia and the diabetic heart. J Mol Cell Cardiol 50(4):598–605. https://doi.org/10.1016/j.yjmcc.2011.01.007 CrossRefPubMed

32.

Costa PZ, Soares R (2013) Neovascularization in diabetes and its complications. Unraveling the angiogenic paradox. Life Sci 92(22):1037–1045. https://doi.org/10.1016/j.lfs.2013.04.001 CrossRefPubMed

33.

Benetti R, Copetti T, Dell’Orso S et al (2005) The calpain system is involved in the constitutive regulation of beta-catenin signaling functions. J Biol Chem 280(23):22070–22080. https://doi.org/10.1074/jbc.M501810200 CrossRefPubMed

34.

Shen Y, Zuo S, Wang Y et al (2016) Thromboxane governs the differentiation of adipose-derived stromal cells toward endothelial cells in vitro and in vivo. Circ Res 118(8):1194–1207. https://doi.org/10.1161/CIRCRESAHA.115.307853 CrossRefPubMed

35.

Galderisi M (2006) Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography. J Am Coll Cardiol 48(8):1548–1551. https://doi.org/10.1016/j.jacc.2006.07.033 CrossRefPubMed

36.

Ganote C, Armstrong S (1993) Ischaemia and the myocyte cytoskeleton: review and speculation. Cardiovasc Res 27(8):1387–1403. https://doi.org/10.1093/cvr/27.8.1387 CrossRefPubMed

37.

Moe GW, Marin-Garcia J (2016) Role of cell death in the progression of heart failure. Heart Fail Rev 21(2):157–167. https://doi.org/10.1007/s10741-016-9532-0 CrossRefPubMed

38.

Crea F, Camici PG, Bairey Merz CN (2014) Coronary microvascular dysfunction: an update. Eur Heart J 35(17):1101–1111. https://doi.org/10.1093/eurheartj/eht513 CrossRefPubMed

39.

Stalker TJ, Skvarka CB, Scalia R (2003) A novel role for calpains in the endothelial dysfunction of hyperglycemia. FASEB J 17(11):1511–1513. https://doi.org/10.1096/fj.02-1213fje CrossRefPubMed

40.

Bodnar RJ, Rodgers ME, Chen WC, Wells A (2013) Pericyte regulation of vascular remodeling through the CXC receptor 3. Arterioscler Thromb Vasc Biol 33(12):2818–2829. https://doi.org/10.1161/ATVBAHA.113.302012 CrossRefPubMedPubMedCentral

41.

Yildirim C, Favre J, Weijers EM et al (2015) IFN-β affects the angiogenic potential of circulating angiogenic cells by activating calpain 1. Am J Physiol Heart Circ Physiol 309(10):H1667–H1678. https://doi.org/10.1152/ajpheart.00810.2014 CrossRefPubMed

42.

Su Y, Cui Z, Li Z, Block ER (2006) Calpain-2 regulation of VEGF-mediated angiogenesis. FASEB J 20(9):1443–1451. https://doi.org/10.1096/fj.05-5354com CrossRefPubMed

43.

Miyazaki T, Honda K, Ohata H (2010) m-Calpain antagonizes RhoA overactivation and endothelial barrier dysfunction under disturbed shear conditions. Cardiovasc Res 85(3):530–541. https://doi.org/10.1093/cvr/cvp311 CrossRefPubMed

44.

Zhang Y, Li Q, Youn JY, Cai H (2017) Protein phosphotyrosine phosphatase 1B (PTP1B) in calpain-dependent feedback regulation of vascular endothelial growth factor receptor (VEGFR2) in endothelial cells: implications in VEGF-dependent angiogenesis and diabetic wound healing. J Biol Chem 292(2):407–416. https://doi.org/10.1074/jbc.M116.766832 CrossRefPubMed

45.

Li G, Iyengar R (2002) Calpain as an effector of the Gq signaling pathway for inhibition of Wnt/beta -catenin-regulated cell proliferation. Proc Natl Acad Sci U S A 99(20):13254–13259. https://doi.org/10.1073/pnas.202355799 CrossRefPubMedPubMedCentral

46.

Rios-Doria J, Kuefer R, Ethier SP, Day ML (2004) Cleavage of beta-catenin by calpain in prostate and mammary tumor cells. Cancer Res 64(20):7237–7240. https://doi.org/10.1158/0008-5472.CAN-04-1048 CrossRefPubMed

47.

Xi XH, Wang Y, Li J, Wang FW, Tian GH, Yin MS, Mu YL, Chong ZZ (2015) Activation of Wnt/beta-catenin/GSK3beta signaling during the development of diabetic cardiomyopathy. Cardiovasc Pathol 24(3):179–186. https://doi.org/10.1016/j.carpath.2014.12.002 CrossRefPubMed

48.

Ying Y, Zhu H, Liang Z, Ma X, Li S (2015) GLP1 protects cardiomyocytes from palmitate-induced apoptosis via Akt/GSK3b/b-catenin pathway. J Mol Endocrinol 55(3):245–262. https://doi.org/10.1530/JME-15-0155 CrossRefPubMedPubMedCentral

49.

Huang CJ, Gurlo T, Haataja L et al (2010) Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes. J Biol Chem 285(1):339–348. https://doi.org/10.1074/jbc.M109.024190 CrossRefPubMed

50.

Shanab AY, Nakazawa T, Ryu M et al (2012) Metabolic stress response implicated in diabetic retinopathy: the role of calpain, and the therapeutic impact of calpain inhibitor. Neurobiol Dis 48(3):556–567. https://doi.org/10.1016/j.nbd.2012.07.025 CrossRefPubMed

Titel: Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis
verfasst von: Xiaomei Teng
Chen Ji
Huiting Zhong
Dong Zheng
Rui Ni
David J. Hill
Sidong Xiong
Guo-Chang Fan
Peter A. Greer
Zhenya Shen
Tianqing Peng
Publikationsdatum: 18.02.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 5/2019
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-019-4828-y

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

24.04.2024 | DGIM 2024 | Kongressbericht | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2019

Alcohol consumption and incident diabetes: The Atherosclerosis Risk in Communities (ARIC) study

DOC2B promotes insulin sensitivity in mice via a novel KLC1-dependent mechanism in skeletal muscle

Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study

Exploring the association between BMI and mortality in Australian women and men with and without diabetes: the AusDiab study

Black African men with early type 2 diabetes have similar muscle, liver and adipose tissue insulin sensitivity to white European men despite lower visceral fat

Genomic annotation of disease-associated variants reveals shared functional contexts

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig und nur bei therapeutischer Konsequenz

Bei Senioren mit Prostatakarzinom auf Anämie achten!

Update Innere Medizin