Top

Cardiovascular Diabetology

Published in:

Open Access 01-12-2015 | Original investigation

Involvement of Rho-associated protein kinase (ROCK) and bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) in high glucose-increased alkaline phosphatase expression and activity in human coronary artery smooth muscle cells

Authors: Yuya Terao, Seimi Satomi-Kobayashi, Ken-ichi Hirata, Yoshiyuki Rikitake

Published in: Cardiovascular Diabetology | Issue 1/2015

Abstract

Background

Vascular calcification is an independent risk factor for cardiovascular disease. Diabetes mellitus increases the incidence of vascular calcification; however, detailed molecular mechanisms of vascular calcification in diabetes mellitus remain unknown. We recently reported that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) regulates osteoblast-like trans-differentiation of human coronary artery smooth muscle cells (HCASMCs).

Methods

We investigated the effect of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), commonly used in patients with atherosclerotic diseases and diabetes mellitus, on alkaline phosphatase (ALP) mRNA expression in aortas of streptozotocin-induced diabetic mice. We also investigated the effects of the statin, Rho-associated protein kinase (ROCK) inhibitors and BMPER knockdown on ALP mRNA expression and activity in HCASMCs cultured in high glucose-containing media.

Results

Alkaline phosphatase mRNA expression was increased in aortas of streptozotocin-induced diabetic mice, and the increase was inhibited by rosuvastatin. ALP mRNA expression and activity were increased in HCASMCs cultured in high glucose-containing media, and the increases were suppressed by rosuvastatin. This suppression was reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate. High glucose-increased ALP mRNA expression and activity were suppressed by ROCK inhibitors. Moreover, BMPER mRNA expression was increased in diabetic mouse aortas and in HCASMCs cultured in high glucose-containing media, but was not inhibited by rosuvastatin or ROCK inhibitors. Knockdown of BMPER suppressed high glucose-increased ALP activity, but not ROCK activity in HCASMCs.

Conclusions

There are at least two independent pathways in high glucose-induced ALP activation in HCASMCs: the Rho–ROCK signaling pathway and the BMPER-dependent pathway.

Chen NX, Moe SM (2003) Arterial calcification in diabetes. Curr Diabetes Rep 3(1):28–32CrossRef

Wang CY, Liu PY, Liao JK (2008) Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 14(1):37–44. doi:10.1016/j.molmed.2007.11.004 PubMedCentralPubMedCrossRef

Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343(6257):425–430. doi:10.1038/343425a0 PubMedCrossRef

Van Aelst L, D’Souza-Schorey C (1997) Rho GTPases and signaling networks. Genes Dev 11(18):2295–2322PubMedCrossRef

Rikitake Y, Liao JK (2005) Rho GTPases, statins, and nitric oxide. Circ Res 97(12):1232–1235. doi:10.1161/01.res.0000196564.18314.23 PubMedCentralPubMedCrossRef

Son BK, Kozaki K, Iijima K, Eto M, Kojima T, Ota H et al (2006) Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ Res 98(8):1024–1031. doi:10.1161/01.RES.0000218859.90970.8d PubMedCrossRef

Kizu A, Shioi A, Jono S, Koyama H, Okuno Y, Nishizawa Y (2004) Statins inhibit in vitro calcification of human vascular smooth muscle cells induced by inflammatory mediators. J Cell Biochem 93(5):1011–1019. doi:10.1002/jcb.20207 PubMedCrossRef

Li H, Tao HR, Hu T, Fan YH, Zhang RQ, Jia G et al (2010) Atorvastatin reduces calcification in rat arteries and vascular smooth muscle cells. Basic Clin Pharmacol Toxicol 107(4):798–802. doi:10.1111/j.1742-7843.2010.00580.x PubMedCrossRef

Liu D, Cui W, Liu B, Hu H, Liu J, Xie R et al (2014) Atorvastatin protects vascular smooth muscle cells from TGF-beta1-stimulated calcification by inducing autophagy via suppression of the beta-catenin pathway. Cell Physiol Biochem 33(1):129–141. doi:10.1159/000356656 PubMedCrossRef

10.

Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ (1998) Effect of HMG-CoA reductase inhibitors on coronary artery disease as assessed by electron-beam computed tomography. N Engl J Med 339(27):1972–1978. doi:10.1056/nejm199812313392703 PubMedCrossRef

11.

Budoff MJ, Lane KL, Bakhsheshi H, Mao S, Grassmann BO, Friedman BC et al (2000) Rates of progression of coronary calcium by electron beam tomography. Am J Cardiol 86(1):8–11PubMedCrossRef

12.

Achenbach S, Ropers D, Pohle K, Leber A, Thilo C, Knez A et al (2002) Influence of lipid-lowering therapy on the progression of coronary artery calcification: a prospective evaluation. Circulation 106(9):1077–1082PubMedCrossRef

13.

Raggi P, Davidson M, Callister TQ, Welty FK, Bachmann GA, Hecht H et al (2005) Aggressive versus moderate lipid-lowering therapy in hypercholesterolemic postmenopausal women: beyond endorsed lipid lowering with ebt scanning (BELLES). Circulation 112(4):563–571. doi:10.1161/circulationaha.104.512681 PubMedCrossRef

14.

Arad Y, Spadaro LA, Roth M, Newstein D, Guerci AD (2005) Treatment of asymptomatic adults with elevated coronary calcium scores with atorvastatin, vitamin C, and vitamin E: the St. Francis Heart Study randomized clinical trial. J Am Coll Cardiol 46(1):166–172. doi:10.1016/j.jacc.2005.02.089 PubMedCrossRef

15.

Houslay ES, Cowell SJ, Prescott RJ, Reid J, Burton J, Northridge DB et al (2006) Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial. Heart 92(9):1207–1212. doi:10.1136/hrt.2005.080929 PubMedCentralPubMedCrossRef

16.

Puri R, Nicholls SJ, Shao M, Kataoka Y, Uno K, Kapadia SR et al (2015) Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol 65(13):1273–1282. doi:10.1016/j.jacc.2015.01.036 PubMedCrossRef

17.

Moser M, Binder O, Wu Y, Aitsebaomo J, Ren R, Bode C et al (2003) BMPER, a novel endothelial cell precursor-derived protein, antagonizes bone morphogenetic protein signaling and endothelial cell differentiation. Mol Cell Biol 23(16):5664–5679PubMedCentralPubMedCrossRef

18.

Serpe M, Umulis D, Ralston A, Chen J, Olson DJ, Avanesov A et al (2008) The BMP-binding protein Crossveinless 2 is a short-range, concentration-dependent, biphasic modulator of BMP signaling in Drosophila. Dev Cell 14(6):940–953. doi:10.1016/j.devcel.2008.03.023 PubMedCentralPubMedCrossRef

19.

Satomi-Kobayashi S, Kinugasa M, Kobayashi R, Hatakeyama K, Kurogane Y, Ishida T et al (2012) Osteoblast-like differentiation of cultured human coronary artery smooth muscle cells by bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER). J Biol Chem 287(36):30336–30345. doi:10.1074/jbc.M111.329110 PubMedCentralPubMedCrossRef

20.

Widyantoro B, Emoto N, Nakayama K, Anggrahini DW, Adiarto S, Iwasa N et al (2010) Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation 121(22):2407–2418. doi:10.1161/circulationaha.110.938217 PubMedCrossRef

21.

Tawa H, Rikitake Y, Takahashi M, Amano H, Miyata M, Satomi-Kobayashi S et al (2010) Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis. Circ Res 106(11):1731–1742. doi:10.1161/circresaha.110.216747 PubMedCrossRef

22.

Rikitake Y, Liao JK (2005) Rho-kinase mediates hyperglycemia-induced plasminogen activator inhibitor-1 expression in vascular endothelial cells. Circulation 111(24):3261–3268. doi:10.1161/circulationaha.105.534024 PubMedCentralPubMedCrossRef

23.

Zhou Q, Liao JK (2010) Pleiotropic effects of statins—basic research and clinical perspectives. Circ J 74(5):818–826PubMedCentralPubMedCrossRef

24.

Helbing T, Rothweiler R, Heinke J, Goetz L, Diehl P, Zirlik A et al (2010) BMPER is upregulated by statins and modulates endothelial inflammation by intercellular adhesion molecule-1. Arterioscler Thromb Vasc Biol 30(3):554–560. doi:10.1161/atvbaha.109.201087 PubMedCentralPubMedCrossRef

25.

Kawamura H, Yokote K, Asaumi S, Kobayashi K, Fujimoto M, Maezawa Y et al (2004) High glucose-induced upregulation of osteopontin is mediated via Rho/Rho kinase pathway in cultured rat aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 24(2):276–281. doi:10.1161/01.ATV.0000112012.33770.2a PubMedCrossRef

26.

Chen NX, Duan D, O’Neill KD, Moe SM (2006) High glucose increases the expression of Cbfa1 and BMP-2 and enhances the calcification of vascular smooth muscle cells. Nephrol Dial Transpl 21(12):3435–3442. doi:10.1093/ndt/gfl429 CrossRef

27.

Sinha A, Vyavahare NR (2013) High-glucose levels and elastin degradation products accelerate osteogenesis in vascular smooth muscle cells. Diabetes Vasc Dis Res 10(5):410–419. doi:10.1177/1479164113485101 CrossRef

28.

Trion A, Schutte-Bart C, Bax WH, Jukema JW, van der Laarse A (2008) Modulation of calcification of vascular smooth muscle cells in culture by calcium antagonists, statins, and their combination. Mol Cell Biochem 308(1–2):25–33. doi:10.1007/s11010-007-9608-1 PubMedCentralPubMedCrossRef

29.

Katsiki N, Tziomalos K, Chatzizisis Y, Elisaf M, Hatzitolios AI (2010) Effect of HMG-CoA reductase inhibitors on vascular cell apoptosis: beneficial or detrimental? Atherosclerosis 211(1):9–14. doi:10.1016/j.atherosclerosis.2009.12.028 PubMedCrossRef

30.

Blanco-Colio LM, Villa A, Ortego M, Hernandez-Presa MA, Pascual A, Plaza JJ et al (2002) 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation. Atherosclerosis 161(1):17–26PubMedCrossRef

31.

Knapp AC, Huang J, Starling G, Kiener PA (2000) Inhibitors of HMG-CoA reductase sensitize human smooth muscle cells to Fas-ligand and cytokine-induced cell death. Atherosclerosis 152(1):217–227PubMedCrossRef

32.

Sindermann JR, Fan L, Weigel KA, Troyer D, Muller JG, Schmidt A et al (2000) Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture. Atherosclerosis 150(2):331–341PubMedCrossRef

33.

Piconi L, Corgnali M, Da Ros R, Assaloni R, Piliego T, Ceriello A (2008) The protective effect of rosuvastatin in human umbilical endothelial cells exposed to constant or intermittent high glucose. J Diabetes Complicat 22(1):38–45. doi:10.1016/j.jdiacomp.2007.03.004 PubMedCrossRef

34.

Vilahur G, Casani L, Pena E, Duran X, Juan-Babot O, Badimon L (2009) Induction of RISK by HMG-CoA reductase inhibition affords cardioprotection after myocardial infarction. Atherosclerosis 206(1):95–101. doi:10.1016/j.atherosclerosis.2009.02.009 PubMedCrossRef

35.

Cormack-Aboud FC, Brinkkoetter PT, Pippin JW, Shankland SJ, Durvasula RV (2009) Rosuvastatin protects against podocyte apoptosis in vitro. Nephrol Dial Transpl 24(2):404–412. doi:10.1093/ndt/gfn528 CrossRef

36.

Pearson JT, Jenkins MJ, Edgley AJ, Sonobe T, Joshi M, Waddingham MT et al (2013) Acute Rho-kinase inhibition improves coronary dysfunction in vivo, in the early diabetic microcirculation. Cardiovasc Diabetol 12:111. doi:10.1186/1475-2840-12-111 PubMedCentralPubMedCrossRef

37.

Cicek FA, Kandilci HB, Turan B (2013) Role of ROCK upregulation in endothelial and smooth muscle vascular functions in diabetic rat aorta. Cardiovasc Diabetol 12:51. doi:10.1186/1475-2840-12-51 PubMedCentralPubMedCrossRef

38.

Shimokawa H, Satoh K (2015) 2015 ATVB plenary lecture: translational research on rho-kinase in cardiovascular medicine. Arterioscler Thromb Vasc Biol 35(8):1756–1769. doi:10.1161/atvbaha.115.305353 PubMedCrossRef

39.

Wallin R, Wajih N, Greenwood GT, Sane DC (2001) Arterial calcification: a review of mechanisms, animal models, and the prospects for therapy. Med Res Rev 21(4):274–301PubMedCrossRef

40.

Wei Q, Ren X, Jiang Y, Jin H, Liu N, Li J (2013) Advanced glycation end products accelerate rat vascular calcification through RAGE/oxidative stress. BMC Cardiovasc Disord 13:13. doi:10.1186/1471-2261-13-13 PubMedCentralPubMedCrossRef

41.

Kovarnik T, Mintz GS, Skalicka H, Kral A, Horak J, Skulec R et al (2012) Virtual histology evaluation of atherosclerosis regression during atorvastatin and ezetimibe administration: HEAVEN study. Circ J 76(1):176–183PubMedCrossRef

Title: Involvement of Rho-associated protein kinase (ROCK) and bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) in high glucose-increased alkaline phosphatase expression and activity in human coronary artery smooth muscle cells
Authors: Yuya Terao
Seimi Satomi-Kobayashi
Ken-ichi Hirata
Yoshiyuki Rikitake
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2015
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-015-0271-7

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Candesartan restores pressure-induced vasodilation and prevents skin pressure ulcer formation in diabetic mice

The amount of C1q–adiponectin complex is higher in the serum and the complex localizes to perivascular areas of fat tissues and the intimal–medial layer of blood vessels of coronary artery disease patients

Comparison of effects of sitagliptin and voglibose on left ventricular diastolic dysfunction in patients with type 2 diabetes: results of the 3D trial

The inflammation, vascular repair and injury responses to exercise in fit males with and without Type 1 diabetes: an observational study

Poorly controlled type 2 diabetes is accompanied by significant morphological and ultrastructural changes in both erythrocytes and in thrombin-generated fibrin: implications for diagnostics

Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage