조현재 서울대학교병원순환기내과, 심혈관연구실,
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1 Molecular Mechanism of Vascular Calcification 조현재 서울대학교병원순환기내과, 심혈관연구실, 서울대학교병원심혈관센터
2 Vascular calcification : clinical hurdles
3 Vascular calcification : clinical significance! Clinical consequences in atherosclerosis Diabetes, and end-stage renal disease Prognostic indicator of future adverse cardiovascular events Increased CAC correlates severity of CAD Paolo R et al, Circulation 2000;101: Increased rate of progression of CAC correlates adverse cardiac event Schmermund A et al, Cardiol Clin 2003;21(4): CAC score: coronary artery calcium score, CAD :coronary artery disease
4 Vascular calcification : current concept Passive consequence of aging Actively regulated process resembling the mineralization of endochondral d and membranous bone Future therapeutic strategy!
5 Vascular calcification: type (A) Atherosclerotic calcification - intimal and subintimal calcification (B) Medial calcification - diabetes, ESRD, non-atherosclerotic? (C) Valvular calcification (D) Calciphylaxis - calcific uremic arteriopathy Johnson RC et al. Circ Res. 2006
6 Vascular calcification : type A. Atherosclerotic Calcification - focal coronary calcification : plaque rupture, coronary dissection under PCI B. Medial Artery Calcification - increased arterial stiffness, PWV, Pulse pressure - strong correlation with CAD, future CV event in CKD/DM, future amputation C. Cardiac Valve Calcification - main mechanism of valve failure - correlate with stroke, atrial fibrillation,cv event D. Calciphylaxis - 1 % of hemodialysis patient - grave prognosis, high mortality due to tissue necrosis
7 Introduction and clinical significance Type of vascular calcification Cellular determinants Molecular determinants and inducers Osteoporosis and vascular calcification Treatment of vascular calcification Conclusion
8 Cellular determinants origin of calcifying cells Origin of osteoblastic or osteogenic cells in vasculature is a great topic of debate. vascular smooth muscle cell (VSMC): contractile proliferative, synthetic form calcifying vascular cell (CVC): may be a certain clone or subpopulation of VSMC pericyte: a kind of mesenchymal progenitors mesenchymal stem cell (circulating or resident), adventitial myofibroblast (resident?) and fibrocyte (circulating) calcifying vascular progenitor cells (circulating, resident)
9 Cellular determinants origin of calcifying cells Cbfa1, Osterix, Msx: transcription factor / ALP, Osteocalcin: functional phenotypic marker BMP 2/4: osteogenic cytokine Seoul National Johnson University RC Hospital et al. Circ Cardiovascular Res Center
10 Cellular determinants origin of calcifying cells VSMC preparation C57BL6 mice Aorta VSMC Passage 6~7 6 well plate D5 D7 D10 Von Kossa stain Calcification media : DMEM, 15% FCS, CaCl2 6mM, β-glycerophosphate 10mM Yoon YE et al. Unpublished data
11 Molecular determinants and inducers (or inhibitors) 1) Inflammatory signal: Oxidized LDL, TNF-α and oxidative stress, etc 2) BMP-2 3) Msx2 4) Runx2/Cbfa1 (core binding factor α1) 5) Osteoclacin 6) Alkaline li phosphatase h (ALP) 7) RANK/RANKL/Osteoprotegerin (OPG) 8) Osteopontin (OPN) *Angiotensin II
12 Inflammatory signal and chronic inflammation Parallel mechanisms in soft tissue versus atherosclerotic and non-atherosclerotic vascular calcification Abedin M. et al ATVB. 2004
![Inflammatory signal and chronic inflammation Inflammation plaque macrophage-derived proteinases [MMP-2/9, Cathepsin B/S etc.] 1.](/docs-images/72/67463586/images/13-2.jpg "Release of biologically active, soluble elastin-derived peptides: promote osteogenic differentiation of VSMCs 2.")
13 Inflammatory signal and chronic inflammation Inflammation plaque macrophage-derived proteinases [MMP-2/9, Cathepsin B/S etc.] 1. Release of biologically active, soluble elastin-derived peptides: promote osteogenic differentiation of VSMCs 2. Degraded medial elastin: favors calcification through an increase of elastin polarity that in turn enhances elastin affinity for calcium Simionescu A et Seoul al BBRC National 2005 University / Aikawa Hospital E. Cardiovascular et al Circulation Center 2009
14 BMP-2 (bone morphogenetic protein 2) the largest subclass of the TGF-β superfamily a well-known inducer for bone and cartilage formation expressed by a variety of cells in atherosclerotic ti lesions, including endothelial cells, foam cells, and VSMCs. BMP-2 and BMP-4: both mineralization and local induction of inflammation BMP-7: induce osteogenic potential, but retard vascular calcification.
15 Msx2 a BMP-2-inducible transcription factor a controller of craniofacial i mineralization BMP-2/Msx/Wnt signaling cascade is upregulated in the context of type 2 diabetes, obesity and hypercholesterolemia plays a key role in early stages of medial calcification. Expression of Msx2 in adventitial cells Shao JS et al. JCI Seoul National University Hospital Shao Cardiovascular JS et al ATVB. Center 2006
16 Runx2/Cbfa1 (core binding factor α1), Osx (osterix) master regulator of osteoblastic differentiation a key transcription factor of various osteogenic and osteoblastic differentiation related genes (osteoclacin, type I collagen, bone sialoprotein, alkaline phosphatase) the full effect of Runx2/Cbfa1 is required activation of a downstream transcription factor, Osterix. Runx2/Cbfa1 expression in VSMCs serves as an early, definitive marker of osteoblastic differentiation and the initial step in vascular calcification. BSP (bone sialoprotein), OPG (osteoprotegerin), OPN (osteopontin), OCN (osteocalcin) Demer LL et al. Circulation. 2008
17 Osteocalcin and alkaline phosphatase (ALP) Osteoclacin: 1) most osteoblast specific gene. noncollagenous protein 2) secreted by osteoblast 3) clinically used as biomarker for the bone formation process Alkaline phosphatase (ALP): 1) a functional phenotypic marker of osteoblasts 2) enzyme that induces tissue biomineralization. 3) ALP degrades inorganic pyrophosphate as a necessary step of calcification and ALP activity is crucial to hydroxyapatite formation. 4) ALP activity is often used as a molecular marker for vascular calcification, as it is an early indicator of ECM deposition.
18 Osteocalcin and alkaline phosphatase (ALP) FACS using antibodies to bone-specific proteins (osteocalcin and alkaline phosphatase) cells were implanted into immunocompromised mouse histologic sections
19 Osteocalcin and alkaline phosphatase (ALP) adventitia media ALP A L Osteocalcin A L Calcifying progenitor cell in the vasculature Cho HJ et al. Unpublished data
20 Osteocalcin and alkaline phosphatase (ALP) ALP staining ALP activity (cell lysate, normalized by protein conc.) Sca-1+/PDGFRα+ Sca-1+/PDGFRα- Sca-1-/PDGFRα+ Sca-1-/PDGFRα- Relative va alue (%) * Sca-1+ PDGFRα- * Sca-1+ PDGFRα+ Sca-1- PDGFRα- Sca-1- PDGFRα+ D0 D1 D3 D7 D14 D0 D1 D3 D7 Charcoal stripped FBS 10% Calcifying progenitor cell in the vasculature Cho HJ et al. Unpublished data
21 Osteopontin (OPN) highly expressed at sites with atherosclerotic plaques, especially those associated with macrophages and foam cells. pro-inflammatory and pro-atherogenic molecule??, Feedback mechanism? a negative regulator in vascular calcification: an inhibitor of calcification and an active inducer of decalcification. OPN-TG mice: atherogenic OPN-KO mice: less atherogenic, high vascular calcification OPN expression, function, and regulation are not clearly understood in the context of atherosclerosis and vascular pathophysiology. Cho HJ et al. Curr Atheroscler Rep. 2009
22 RANK/RANKL/Osteoprotegerin Key regulator of bone metabolism Receptor Activator of Nuclear factor-κb (RANK): expressed on osteoclast RANK ligand (RANKL): from osteoblast, osteoclastogenesis stimulatory factor Osteoprotegerin (OPG): 1) a member of TNF receptor superfamily 2) produced by various cells (EC, VSMC, osteoblast, dendritic cell) 3) soluble receptor: competing with RANK, neutralizing RANKL, preventing RANKL-RANK interaction osteoclastogenesis inhibitory activity 4) autocrine EC survival factor OPG-TG / RANKL-KO / RANKL-KO mice: osteopetrosis OPG KO mice: osteoporosis, arterial calcification OPG: protective factor for bone and vascular system: mechanism?? Elevated serum OPG: high cardiovascular mortality, high osteoporosis
23 RANK/RANKL/Osteoprotegerin Seoul National Hofbauer University LC Hospital et Cardiovascular. JAMA Center
24 Molecular determinants and inducers - summary 1) Inflammatory signal: pro-calcific environment 2) BMP-2: strong inducer for bone formation 3) Msx2: BMP-2-inducible transcription factor in medial calcification 4) Runx2/Cbfa: 5) Osteocalcin: osteoblast-specific transcription factor osteoblast-specific marker 6) Alkaline phosphatase (ALP): functional osteoblast phenotypic marker 7) RANK/RANKL/Osteoprotegerin (OPG): balancing factors in osteoblast and osteoclast & osteoporosis and arterial calcification 8) Osteopontin (OPN): pro-inflammatory and pro-atherogenic, but anti-calcific and decalcific factor?
25 Osteoporosis and vascular calcification Osteoporosis is frequently associated with vascular calcification, and there is a positive association between the severity of aortic calcification and bone loss Denosumab (RANKL monoclonal Ab) reduction of osteoporosis and vascular calcification Mechanism is a conundrum! Hypothesis vascular calcification promotes bone loss bone loss promotes vascular calcification a common etiology (estrogen deficiency?, LDL? OPG/RANKL )
26 Angiotensin II and vascular calcification Angiotensin-aldosterone system corticosteroid aldosterone ACEI, Aldosterone antagonist Mineralocorticoid receptor Vascular calcification VSMC Ischemic cardiovascular events Osteoblastic differentiation Jaffe, Demer et al. Arterioscler Thromb Vasc Biol. 2007;27:799
27 Angiotensin II stimulates VSMCs calcification ALP activity ALP stain ALP: Alkaline phosphatase
28 Angiotensin II stimulates VSMCs calcification Von Kossa Stain
29 Angiotensin II stimulates VSMCs calcification through AT1 receptor signaling ALP Activity ALP Staining Von Kossa 6wk #3 mvsmcs, D3 6wk #6 mvsmcs, D5 20wk #6 mvsmcs, D10 2 Control Ang II 1nM Ang II (nm) Losartan (μm) Ang II 1nM Losartan 10μM
30 Angiotensin II stimulates VSMCs calcification through AT1 receptor signaling 6wks mvsmcs #4, D3 ALP: Alkaline phosphatase
31 Treatment of vascular calcification Kapustin Seoul National A, Shanahan University CM. Hospital Curr Cardiovascular Opin Pharmacol. Center 2009
32 Treatment of vascular calcification Kapustin Seoul National A, Shanahan University CM. Hospital Curr Cardiovascular Opin Pharmacol. Center 2009
33 Treatment of vascular calcification clinical trials Coronary artery calcium (CAC) and/or abdominal aortic calcium (AAC) Although the target reduction in LDL was achieved, there was no treatment effect on the rate of calcified plaque progression Statin could not attenuate CAC progression
34 Treatment of valvular calcification clinical trials Aortic valve calcification: aortic stenosis [ 가설 ] lipid-lowering treatment might prevent progression of aortic-valve stenosis and thus reduce the need for aortic-valve replacement. [ 결과 ] Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic valve events and ischemic events in patients with aortic stenosis.
35 Treatment of vascular calcification new target Seoul National University Doherty Hospital Cardiovascular TM et al. PNAS. Center 2003
36 Cellular determinants origin of calcifying cells Origin of osteoblastic or osteogenic cells in vasculature is a great topic of debate. vascular smooth muscle cell (VSMC): contractile proliferative, synthetic form calcifying vascular cell (CVC): may be a certain clone or subpopulation of VSMC pericyte: a kind of mesenchymal progenitors mesenchymal stem cell (circulating or resident), adventitial myofibroblast (resident?) and fibrocyte (circulating) calcifying vascular progenitor cells (circulating, resident)
37 Treatment of vascular calcification new cellular target Sca-1+/PDGFRα+ Osteoblastic progenitor cells Sca-1+/PDGFRα- Osteoblastic/ osteoclastic progenitor cell ( bi-directional cell ) Sca-1-/PDGFRα+ VSMC Sca-1-/PDGFRα- Fibroblast L Adventitia Adventitia and Media A Sca-1+PDGFRα + Sca-1+PDGFRα - Sca-1-PDGFRα + Sca-1-PDGFRα -
38 Vascular calcifying progenitor cells
39 Osteoblastic differentiation of calcifying progenitor cells
40 Osteoclastic differentiation of calcifying progenitor cells
41 PPARγ activation suppresses osteoblastic differentiation and promotes osteoclastic differentiation R=Rosiglitazone (PPARγ agonist)
42 Bone Marrow Sca-1+/PDGFRα+ AD DVENTIITIA Sca-1+/PDGFRα- Calcified cells Calcified cells MED DIA Calcified cells Calcified cells Osteoblastic progenitor cells Sca-1+/PDGFRα+ Osteoblastic/ osteoclastic progenitor cell ( bi bi-direction direction cell ) Sca-1+/PDGFRα- VSMC Fibroblast Osteoclast RANKL RANK OPG Sca-1-/PDGFRα+ Sca-1-/PDGFRα- BMP-2
43 Introduction and clinical significance Type of vascular calcification Cellular determinants Molecular determinants and inducers (or inhibitors) Osteoporosis and vascular calcification Treatment of vascular calcification Conclusion
44 Conclusions 1. Vascular calcification is an important feature of progressive atherosclerosis, a poor prognostic factor of future adverse cardiovascular events. 2. Recent studies have shown that the pathophysiologic process of vascular calcification is tightly-regulated, active process. 3. Recent advances in understanding molecular and cellular mechanisms of vascular calcification may lead to the development of new therapeutic strategies for cardiovascular diseases. 4. Eventually, we hope that vascular calcification, once considered irreversible process, would be regressed and reserved through decalcifying therapy in the future.
45 Acknowledgements Seoul National University Cardiovascular Research Lab
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47
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49 Treatment of vascular calcification - hypothesis Seoul National University Cho Hospital HJ et Cardiovascular al. Unpublished Center data
50 Mechanism of osteogenesis, showing the major genes, growth factors, and signaling pathways culminating in fully mature chondrocytes, osteoblasts, and osteoclasts Doherty T M et al. PNAS 2003;100: by National Academy of Sciences
51 Vascular calcification : clinical significance? 정기검진상우연히발견된 High calcium score (CAC score = 3609) CAC score: coronary artery calcium score
52 Vascular calcification : clinical hurdles 4 가지타임이있다이중문제가되는것은 vascular 이다.
53 Vascular calcification : clinical hurdles 4 가지타임이있다이중문제가되는것은 vascular 이다.
54 Vascular calcification : clinical hurdles 4 가지타임이있다이중문제가되는것은 vascular 이다. Heavy calcification not just a marker of severe disease, but an enemy of treatment
55 Molecular determinants and inducers - summary 1) Inflammatory signal: pro-calcific environment 2) BMP-2: inducer for bone formation 3) Msx2: BMP-2-inducible transcription factor in medial calcification 4) Runx2/Cbfa: osteoblast-specific transcription factor 5) Osteoclacin: osteoblast-specific marker 6) Alkaline phosphatase (ALP): functional osteoblast phenotypic marker 7) RANK/RANKL/Osteoprotegerin (OPG): balancing factors in osteoporosis, arterial calcification 8) Osteopontin (OPN): pro-inflammatory and pro-atherogenic, but anti- calcific and decalcific factor?
56 Vascular calcification : clinical significance
57 CAC score as a prognostic marker Unadjusted for Risk Adjusted for Risk Survival according to baseline CAC score Shaw et al, Radiology, 2003
58 CAC score and CV event Death + MI Death + MI + Revasc Cooper Clinic Study LaMonte et al, Am J Epidemiol 2005
59 Vascular calcification : clinical significance mlad 70%, dlcx 50%, mrca 50% with calcification
60 SHAPE Guideline Seoul National Naghavi University et Hospital al, Am Cardiovascular J Cardiolgoy, Center2006
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