The Context-dependent Role of Transforming Growth Factor-β/miR-378a-3p/connective Tissue Growth Factor in Vascular Calcification: a Translational Study

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2023 Feb 14

PMID 36787443

Authors

You-Tien Tsai

Hsiang-Yuan Yeh

Chia-Ter Chao

Jenq-Wen Huang

Chih-Kang Chiang

Affiliations

Soon will be listed here.

Abstract

Background: Vascular calcification (VC) constitutes an important vascular pathology with prognostic importance. The pathogenic role of transforming growth factor-β (TGF-β) in VC remains unclear, with heterogeneous findings that we aimed to evaluate using experimental models and clinical specimens.

Methods: Two approaches, exogenous administration and endogenous expression upon osteogenic media (OM) exposure, were adopted. Aortic smooth muscle cells (ASMCs) were subjected to TGF-β1 alone, OM alone, or both, with calcification severity determined. We evaluated miR-378a-3p and TGF-β1 effectors (connective tissue growth factor; CTGF) at different periods of calcification. Results were validated in an model and further in sera from older adults without or with severe aortic arch calcification.

Results: TGF-β1 treatment induced a significant dose-responsive increase in ASMC calcification without or with OM at the mature but not early or mid-term VC period. On the other hand, OM alone induced VC accompanied by suppressed TGF-β1 expressions over time; this phenomenon paralleled the declining miR-378a-3p and CTGF expressions since early VC. TGF-β1 treatment led to an upregulation of CTGF since early VC but not miR-378a-3p until mid-term VC, while miR-378a-3p overexpression suppressed CTGF expressions without altering TGF-β1 levels. The OM-induced down-regulation of TGF-β1 and CTGF was also observed in the models, with compatible results identified from human sera.

Conclusions: We showed that TGF-β1 played a context-dependent role in VC, involving a time-dependent self-regulatory loop of TGF-β1/miR-378a-3p/CTGF signaling. Our findings may assist subsequent studies in devising potential therapeutics against VC.

Citing Articles

Profibrotic role of transcription factor SP1 in cross-talk between fibroblasts and M2 macrophages.

Feng P, Che Y, Gao C, Chu X, Li Z, Li L iScience. 2023; 26(12):108484.

PMID: 38094246 PMC: 10716550. DOI: 10.1016/j.isci.2023.108484.

References

Dellegrottaglie S, Saran R, Rajagopalan S . Vascular calcification in patients with renal failure: culprit or innocent bystander?. Cardiol Clin. 2005; 23(3):373-84. DOI: 10.1016/j.ccl.2005.04.001. View

Shang X, Scott D, Hodge A, Khan B, Khan N, English D . Adiposity assessed by anthropometric measures has a similar or greater predictive ability than dual-energy X-ray absorptiometry measures for abdominal aortic calcification in community-dwelling older adults. Int J Cardiovasc Imaging. 2016; 32(9):1451-1460. DOI: 10.1007/s10554-016-0920-2. View

Huang J, Huang H, Wu M, Li J, Xie H, Zhou H . Connective tissue growth factor induces osteogenic differentiation of vascular smooth muscle cells through ERK signaling. Int J Mol Med. 2013; 32(2):423-9. DOI: 10.3892/ijmm.2013.1398. View

Rodriguez A, Scott D, Khan B, Khan N, Hodge A, English D . Low Relative Lean Mass is Associated with Increased Likelihood of Abdominal Aortic Calcification in Community-Dwelling Older Australians. Calcif Tissue Int. 2016; 99(4):340-9. DOI: 10.1007/s00223-016-0157-z. View

Kanazawa S, Miyake T, Kakinuma T, Tanemoto K, Tsunoda T, Kikuchi K . The expression of platelet-derived growth factor and connective tissue growth factor in different types of abdominal aortic aneurysms. J Cardiovasc Surg (Torino). 2005; 46(3):271-8. View

Jiao L, Zhuang Y, Jiang M, Zhou J, Wu M, Chen Z . Angiopoietin-like 2 has auxo-action in atherosclerosis by promoting atherosclerotic calcification. Int J Clin Exp Pathol. 2020; 10(8):9084-9091. PMC: 6965476. View

Herrmann J, Babic M, Tolle M, van der Giet M, Schuchardt M . Research Models for Studying Vascular Calcification. Int J Mol Sci. 2020; 21(6). PMC: 7139511. DOI: 10.3390/ijms21062204. View

Brandman O, Meyer T . Feedback loops shape cellular signals in space and time. Science. 2008; 322(5900):390-5. PMC: 2680159. DOI: 10.1126/science.1160617. View

Ciceri P, Elli F, Cappelletti L, Tosi D, Braidotti P, Bulfamante G . A new in vitro model to delay high phosphate-induced vascular calcification progression. Mol Cell Biochem. 2015; 410(1-2):197-206. DOI: 10.1007/s11010-015-2552-6. View

10.

Kim S, Kim H, Huang W, Okada M, Welge J, Wang Y . Cardiac stem cells with electrical stimulation improve ischaemic heart function through regulation of connective tissue growth factor and miR-378. Cardiovasc Res. 2013; 100(2):241-51. PMC: 3797629. DOI: 10.1093/cvr/cvt192. View

11.

Chao C, Liu Y, Su S, Yeh H, Chen H, Lee P . Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification. Arterioscler Thromb Vasc Biol. 2017; 37(7):1402-1414. DOI: 10.1161/ATVBAHA.117.309566. View

12.

Chao C, Han D, Huang J . Circulating microRNA-125b Levels Are Associated With the Risk of Vascular Calcification in Healthy Community-Dwelling Older Adults. Front Cardiovasc Med. 2021; 8:624313. PMC: 7937626. DOI: 10.3389/fcvm.2021.624313. View

13.

Chao C, Yeh H, Tsai Y, Chuang P, Yuan T, Huang J . Natural and non-natural antioxidative compounds: potential candidates for treatment of vascular calcification. Cell Death Discov. 2019; 5:145. PMC: 6853969. DOI: 10.1038/s41420-019-0225-z. View

14.

Tsai Y, Yeh H, Chao C, Chiang C . Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic Strategies. Oxid Med Cell Longev. 2021; 2021:6675548. PMC: 7935587. DOI: 10.1155/2021/6675548. View

15.

Chang Z, Yan G, Zheng J, Liu Z . The lncRNA GAS5 Inhibits the Osteogenic Differentiation and Calcification of Human Vascular Smooth Muscle Cells. Calcif Tissue Int. 2020; 107(1):86-95. DOI: 10.1007/s00223-020-00696-1. View

16.

Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky V . Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol. 2002; 22(6):975-82. DOI: 10.1161/01.atv.0000019729.39500.2f. View

17.

London G, Guerin A, Marchais S, Metivier F, Pannier B, Adda H . Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003; 18(9):1731-40. DOI: 10.1093/ndt/gfg414. View

18.

Muller-Deile J, Dannenberg J, Schroder P, Lin M, Miner J, Chen R . Podocytes regulate the glomerular basement membrane protein nephronectin by means of miR-378a-3p in glomerular diseases. Kidney Int. 2017; 92(4):836-849. PMC: 5658661. DOI: 10.1016/j.kint.2017.03.005. View

19.

Shimokado A, Sun Y, Nakanishi M, Sato F, Oikawa K, Akasaka T . Smad3 plays an inhibitory role in phosphate-induced vascular smooth muscle cell calcification. Exp Mol Pathol. 2014; 97(3):458-64. DOI: 10.1016/j.yexmp.2014.10.005. View

20.

Hashimoto H, Iijima K, Hashimoto M, Son B, Ota H, Ogawa S . Validity and usefulness of aortic arch calcification in chest X-ray. J Atheroscler Thromb. 2009; 16(3):256-64. DOI: 10.5551/jat.e570. View