Korean Circ J.  2021 Feb;51(2):114-125. 10.4070/kcj.2020.0517.

Role of Inflammation in Arterial Calcification

• Lee HY
• Lim S
• Park S

• KMID: 2512449
• DOI: http://doi.org/10.4070/kcj.2020.0517

Abstract

Arterial calcification, characterized by calcium phosphate deposition in the arteries, can be divided into intimal calcification and medial calcification. The former is the predominant form of calcification in coronary artery plaques; the latter mostly affects peripheral arteries and aortas. Both forms of arterial calcification have strong correlations with adverse cardiovascular events. Intimal microcalcification is associated with increased risk of plaque disruption while the degree of burden of coronary calcification, measured by coronary calcium score, is a marker of overall plaque burden. Continuous research on vascular calcification has been performed during the past few decades, and several cellular and molecular mechanisms and therapeutic targets were identified. However, despite clinical trials to evaluate the efficacy of drug therapies to treat vascular calcification, none have been shown to have efficacy until the present. Therefore, more extensive research is necessary to develop appropriate therapeutic strategies based on a thorough understanding of vascular calcification. In this review, we mainly focus on intimal calcification, namely the pathobiology of arterial calcification, and its clinical implications.

Keyword

Arterial calcification; Pathobiology; Therapeutic strategy; Clinical implication

Reference

1. Cozzolino M, Ciceri P, Galassi A, et al. The key role of phosphate on vascular calcification. Toxins (Basel). 2019; 11:213.

2. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension. 2001; 38:938–942. PMID: 11641313.

3. Shantouf RS, Budoff MJ, Ahmadi N, et al. Total and individual coronary artery calcium scores as independent predictors of mortality in hemodialysis patients. Am J Nephrol. 2010; 31:419–425. PMID: 20389057.

4. Madhavan MV, Tarigopula M, Mintz GS, Maehara A, Stone GW, Généreux P. Coronary artery calcification: pathogenesis and prognostic implications. J Am Coll Cardiol. 2014; 63:1703–1714. PMID: 24530667.

5. Mori H, Torii S, Kutyna M, Sakamoto A, Finn AV, Virmani R. Coronary artery calcification and its progression: What does it really mean? JACC Cardiovasc Imaging. 2018; 11:127–142. PMID: 29301708.

6. Ehara S, Kobayashi Y, Yoshiyama M, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. 2004; 110:3424–3429. PMID: 15557374.

7. Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998; 31:126–133. PMID: 9426030.

8. Hutcheson JD, Goettsch C, Bertazzo S, et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat Mater. 2016; 15:335–343. PMID: 26752654.

9. Lee KY, Chang K. Understanding vulnerable plaques: current status and future directions. Korean Circ J. 2019; 49:1115–1122. PMID: 31760703.

10. Durham AL, Speer MY, Scatena M, Giachelli CM, Shanahan CM. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res. 2018; 114:590–600. PMID: 29514202.

11. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008; 358:1336–1345. PMID: 18367736.

12. Barrett HE, Van der Heiden K, Farrell E, Gijsen FJ, Akyildiz AC. Calcifications in atherosclerotic plaques and impact on plaque biomechanics. J Biomech. 2019; 87:1–12. PMID: 30904335.

13. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation. 2019; 139:e1046–81. PMID: 30565953.

14. Demer LL, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation. 2008; 117:2938–2948. PMID: 18519861.

15. Leszczynska A, Murphy JM. Vascular calcification: Is it rather a stem/progenitor cells driven phenomenon? Front Bioeng Biotechnol. 2018; 6:10. PMID: 29479528.

16. Lee SJ, Lee IK, Jeon JH. Vascular calcification-new insights into its mechanism. Int J Mol Sci. 2020; 21:2685.

17. Bakhshian Nik A, Hutcheson JD, Aikawa E. Extracellular vesicles as mediators of cardiovascular calcification. Front Cardiovasc Med. 2017; 4:78. PMID: 29322046.

18. Yao J, Guihard PJ, Blazquez-Medela AM, et al. Serine protease activation essential for endothelial-mesenchymal transition in vascular calcification. Circ Res. 2015; 117:758–769. PMID: 26265629.

19. Cho HJ, Cho HJ, Lee HJ, et al. Vascular calcifying progenitor cells possess bidirectional differentiation potentials. PLoS Biol. 2013; 11:e1001534. PMID: 23585735.

20. Sata M, Saiura A, Kunisato A, et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med. 2002; 8:403–409. PMID: 11927948.

21. Ma WQ, Sun XJ, Wang Y, Zhu Y, Han XQ, Liu NF. Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis. Mol Cell Endocrinol. 2019; 479:39–53. PMID: 30170182.

22. Lomashvili K, Garg P, O'Neill WC. Chemical and hormonal determinants of vascular calcification in vitro. Kidney Int. 2006; 69:1464–1470. PMID: 16531981.

23. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999; 340:115–126. PMID: 9887164.

24. Zhu D, Mackenzie NC, Millán JL, Farquharson C, MacRae VE. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One. 2011; 6:e19595. PMID: 21611184.

25. Lutgens E, Lutgens SP, Faber BC, et al. Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation. 2006; 113:98–107. PMID: 16365196.

26. Olauson H, Vervloet MG, Cozzolino M, Massy ZA, Ureña Torres P, Larsson TE. New insights into the FGF23-Klotho axis. Semin Nephrol. 2014; 34:586–597. PMID: 25498378.

27. Hruska KA, Mathew S, Saab G. Bone morphogenetic proteins in vascular calcification. Circ Res. 2005; 97:105–114. PMID: 16037577.

28. Shioi A, Katagi M, Okuno Y, et al. Induction of bone-type alkaline phosphatase in human vascular smooth muscle cells: roles of tumor necrosis factor-alpha and oncostatin M derived from macrophages. Circ Res. 2002; 91:9–16. PMID: 12114316.

29. Tyson KL, Reynolds JL, McNair R, Zhang Q, Weissberg PL, Shanahan CM. Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003; 23:489–494. PMID: 12615658.

30. Sandberg WJ, Yndestad A, Øie E, et al. Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization. Arterioscler Thromb Vasc Biol. 2006; 26:857–863. PMID: 16424351.

31. Heiss A, DuChesne A, Denecke B, et al. Structural basis of calcification inhibition by alpha 2-HS glycoprotein/fetuin-A. Formation of colloidal calciprotein particles. J Biol Chem. 2003; 278:13333–13341. PMID: 12556469.

32. Liu H, Wang H, Yang S, Qian D. Downregulation of miR-542-3p promotes osteogenic transition of vascular smooth muscle cells in the aging rat by targeting BMP7. Hum Genomics. 2019; 13:67. PMID: 31829291.

33. Donato AJ, Eskurza I, Silver AE, et al. Direct evidence of endothelial oxidative stress with aging in humans: relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-kappaB. Circ Res. 2007; 100:1659–1666. PMID: 17478731.

34. Csiszar A, Ungvari Z, Edwards JG, et al. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res. 2002; 90:1159–1166. PMID: 12065318.

35. van der Loo B, Labugger R, Skepper JN, et al. Enhanced peroxynitrite formation is associated with vascular aging. J Exp Med. 2000; 192:1731–1744. PMID: 11120770.

36. Alesutan I, Feger M, Tuffaha R, et al. Augmentation of phosphate-induced osteo-/chondrogenic transformation of vascular smooth muscle cells by homoarginine. Cardiovasc Res. 2016; 110:408–418. PMID: 27001421.

37. Atzler D, Gore MO, Ayers CR, et al. Homoarginine and cardiovascular outcome in the population-based Dallas Heart Study. Arterioscler Thromb Vasc Biol. 2014; 34:2501–2507. PMID: 25189571.

38. Collin P, Nefussi JR, Wetterwald A, et al. Expression of collagen, osteocalcin, and bone alkaline phosphatase in a mineralizing rat osteoblastic cell culture. Calcif Tissue Int. 1992; 50:175–183. PMID: 1373988.

39. Shimomura A, Matsui I, Hamano T, et al. Dietary L-lysine prevents arterial calcification in adenine-induced uremic rats. J Am Soc Nephrol. 2014; 25:1954–1965. PMID: 24652795.

40. Moali C, Boucher JL, Sari MA, Stuehr DJ, Mansuy D. Substrate specificity of NO synthases: detailed comparison of L-arginine, homo-L-arginine, their N omega-hydroxy derivatives, and N omega-hydroxynor-L-arginine. Biochemistry. 1998; 37:10453–10460. PMID: 9671515.

41. Kanno Y, Into T, Lowenstein CJ, Matsushita K. Nitric oxide regulates vascular calcification by interfering with TGF-signalling. Cardiovasc Res. 2008; 77:221–230. PMID: 18006450.

42. Van den Bergh G, Opdebeeck B, D'Haese PC, Verhulst A. The vicious cycle of arterial stiffness and arterial media calcification. Trends Mol Med. 2019; 25:1133–1146. PMID: 31522956.

43. Medici D, Potenta S, Kalluri R. Transforming growth factor-β2 promotes Snail-mediated endothelial-mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling. Biochem J. 2011; 437:515–520. PMID: 21585337.

44. Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005; 25:932–943. PMID: 15731494.

45. Kim NG, Gumbiner BM. Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J Cell Biol. 2015; 210:503–515. PMID: 26216901.

46. Hecht E, Freise C, Websky KV, et al. The matrix metalloproteinases 2 and 9 initiate uraemic vascular calcifications. Nephrol Dial Transplant. 2016; 31:789–797. PMID: 26333546.

47. Wang M, Monticone RE, Lakatta EG. Arterial aging: a journey into subclinical arterial disease. Curr Opin Nephrol Hypertens. 2010; 19:201–207. PMID: 20040868.

48. Kim I, Park CS, Lee HY. Angiotensin II type 1 receptor blocker, fimasartan, reduces vascular smooth muscle cell senescence by inhibiting the CYR61 signaling pathway. Korean Circ J. 2019; 49:615–626. PMID: 31074217.

49. Libby P. Interleukin-1 beta as a target for atherosclerosis therapy: biological basis of CANTOS and beyond. J Am Coll Cardiol. 2017; 70:2278–2289. PMID: 29073957.

50. Aikawa E, Nahrendorf M, Figueiredo JL, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007; 116:2841–2850. PMID: 18040026.

51. Abdelbaky A, Corsini E, Figueroa AL, et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ Cardiovasc Imaging. 2013; 6:747–754. PMID: 23833282.

52. Demer LL, Tintut Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler Thromb Vasc Biol. 2014; 34:715–723. PMID: 24665125.

53. Sun Y, Byon CH, Yuan K, et al. Smooth muscle cell-specific runx2 deficiency inhibits vascular calcification. Circ Res. 2012; 111:543–552. PMID: 22773442.

54. Chen NX, Moe SM. Pathophysiology of vascular calcification. Curr Osteoporos Rep. 2015; 13:372–380. PMID: 26409849.

55. Parhami F, Basseri B, Hwang J, Tintut Y, Demer LL. High-density lipoprotein regulates calcification of vascular cells. Circ Res. 2002; 91:570–576. PMID: 12364384.

56. Tintut Y, Patel J, Parhami F, Demer LL. Tumor necrosis factor-alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation. 2000; 102:2636–2642. PMID: 11085968.

57. Zhang X, Li J, Qin JJ, et al. Oncostatin M receptor β deficiency attenuates atherogenesis by inhibiting JAK2/STAT3 signaling in macrophages. J Lipid Res. 2017; 58:895–906. PMID: 28258089.

58. Menini S, Iacobini C, Ricci C, et al. The galectin-3/RAGE dyad modulates vascular osteogenesis in atherosclerosis. Cardiovasc Res. 2013; 100:472–480. PMID: 23975852.

59. Motro M, Shemesh J. Calcium channel blocker nifedipine slows down progression of coronary calcification in hypertensive patients compared with diuretics. Hypertension. 2001; 37:1410–1413. PMID: 11408386.

60. Motro M, Kirwan BA, de Brouwer S, Poole-Wilson PA, Shemesh J; ACTION CC side-arm study. Tracking coronary calcification and atherosclerotic lesions in patients with stable angina pectoris undergoing nifedipine therapy. Cardiology. 2007; 107:165–171. PMID: 16940720.

61. Heymes C, Silvestre JS, Llorens-Cortes C, et al. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology. 1998; 139:2579–2587. PMID: 9564874.

62. Min LJ, Mogi M, Iwai M, Horiuchi M. Signaling mechanisms of angiotensin II in regulating vascular senescence. Ageing Res Rev. 2009; 8:113–121. PMID: 19162241.

63. Armstrong ZB, Boughner DR, Drangova M, Rogers KA. Angiotensin II type 1 receptor blocker inhibits arterial calcification in a pre-clinical model. Cardiovasc Res. 2011; 90:165–170. PMID: 21156821.

64. Lin X, Zhan JK, Zhong JY, et al. lncRNA-ES3/miR-34c-5p/BMF axis is involved in regulating high-glucose-induced calcification/senescence of VSMCs. Aging (Albany NY). 2019; 11:523–535. PMID: 30654331.

65. Belmokhtar K, Ortillon J, Jaisson S, et al. Receptor for advanced glycation end products: a key molecule in the genesis of chronic kidney disease vascular calcification and a potential modulator of sodium phosphate co-transporter PIT-1 expression. Nephrol Dial Transplant. 2019; 34:2018–2030. PMID: 30778553.

66. Goldberg RB, Aroda VR, Bluemke DA, et al. Effect of long-term metformin and lifestyle in the diabetes prevention program and its outcome study on coronary artery calcium. Circulation. 2017; 136:52–64. PMID: 28476766.

67. Watson KE, Boström K, Ravindranath R, Lam T, Norton B, Demer LL. TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify. J Clin Invest. 1994; 93:2106–2113. PMID: 8182141.

68. Hénaut L, Massy ZA. Magnesium as a calcification inhibitor. Adv Chronic Kidney Dis. 2018; 25:281–290. PMID: 29793668.

69. Tzanakis IP, Stamataki EE, Papadaki AN, Giannakis N, Damianakis NE, Oreopoulos DG. Magnesium retards the progress of the arterial calcifications in hemodialysis patients: a pilot study. Int Urol Nephrol. 2014; 46:2199–2205. PMID: 25118610.

70. Puri R, Nicholls SJ, Shao M, et al. Impact of statins on serial coronary calcification during atheroma progression and regression. J Am Coll Cardiol. 2015; 65:1273–1282. PMID: 25835438.

71. Henein M, Granåsen G, Wiklund U, et al. High dose and long-term statin therapy accelerate coronary artery calcification. Int J Cardiol. 2015; 184:581–586. PMID: 25769003.

72. Rhee EJ, Kim HC, Kim JH, et al. 2018 Guidelines for the management of dyslipidemia. Korean J Intern Med. 2019; 34:723–771. PMID: 31272142.

73. Jeong HS, Hong SJ. Benefit of early statin therapy in acute myocardial infarction in Korea. Korean Circ J. 2019; 49:434–436. PMID: 30891965.

74. Orakzai SH, Nasir K, Blaha M, Blumenthal RS, Raggi P. Non-HDL cholesterol is strongly associated with coronary artery calcification in asymptomatic individuals. Atherosclerosis. 2009; 202:289–295. PMID: 18452924.

75. Aengevaeren VL, Mosterd A, Braber TL, et al. Relationship between lifelong exercise volume and coronary atherosclerosis in athletes. Circulation. 2017; 136:138–148. PMID: 28450347.

76. Schwartz RS, Kraus SM, Schwartz JG, et al. Increased coronary artery plaque volume among male marathon runners. Mo Med. 2014; 111:89–94. PMID: 30323509.

77. Arnson Y, Rozanski A, Gransar H, et al. Comparison of the coronary artery calcium score and number of calcified coronary plaques for predicting patient mortality risk. Am J Cardiol. 2017; 120:2154–2159. PMID: 29096884.

78. Villa JK, Diaz MA, Pizziolo VR, Martino HS. Effect of vitamin K in bone metabolism and vascular calcification: A review of mechanisms of action and evidences. Crit Rev Food Sci Nutr. 2017; 57:3959–3970. PMID: 27437760.

79. Riphagen IJ, Keyzer CA, Drummen NE, et al. Prevalence and Effects of Functional Vitamin K Insufficiency: The PREVEND Study. Nutrients. 2017; 9:1334.

80. Tantisattamo E, Han KH, O'Neill WC. Increased vascular calcification in patients receiving warfarin. Arterioscler Thromb Vasc Biol. 2015; 35:237–242. PMID: 25324574.

81. Demer LL, Tintut Y. Interactive and multifactorial mechanisms of calcific vascular and valvular disease. Trends Endocrinol Metab. 2019; 30:646–657. PMID: 31279666.

82. Kassimis G, Didagelos M, De Maria GL, et al. Shockwave intravascular lithotripsy for the treatment of severe vascular calcification. Angiology. 2020; 71:677–688. PMID: 32567327.

83. Yeoh J, Hill J, Spratt JC. Intravascular lithotripsy assisted chronic total occlusion revascularization with reverse controlled antegrade retrograde tracking. Catheter Cardiovasc Interv. 2019; 93:1295–1297. PMID: 30838746.