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Research Paper|Volume 15, Issue 3|pp 830—845

The context-dependent role of transforming growth factor-β/miR-378a-3p/connective tissue growth factor in vascular calcification: a translational study

You-Tien Tsai1, Hsiang-Yuan Yeh2, Chia-Ter Chao1,3,4, Jenq-Wen Huang3,5, Chih-Kang Chiang4,6
  • 1Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  • 2Department of Data Science, Soochow University, Taipei, Taiwan
  • 3Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
  • 4Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei, Taiwan
  • 5Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
  • 6Department of Integrative Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan
Received: October 14, 2022Accepted: February 6, 2023Published: February 13, 2023
https://doi.org/10.18632/aging.204518

Copyright: © 2023 Tsai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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 ex vivo 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 ex vivo 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.