Latent Transforming Growth Factor Binding Protein ? 2 promotes microfibrillar TGF-? bioavailability to drive pathologic fibrosis in remote regions of infarcted hearts
- 1University of Toronto Inforum
Abstract
Myocardial infarction (MI) initiates ventricular remodeling that extends beyond the infarct into remote, viable myocardium, where diffuse extracellular matrix (ECM) remodeling and stiffening contribute to progressive dysfunction and heart failure. Latent transforming growth factor binding protein 2 (LTBP2) is an injury-induced, microfibril-associated ECM glycoprotein that, among the LTBP family, does not covalently bind latent TGF-?. We asked whether LTBP2 regulates remote remodeling after MI, and how a protein lacking latent TGF-??binding capacity could influence TGF-??dependent fibrosis. Wild-type and Ltbp2-null mice underwent permanent coronary ligation or sham surgery and were followed for 28 days by echocardiography and speckle-tracking strain analysis. Remote myocardium was assessed by histology, atomic force microscopy, and quantitative proteomics. Mechanism was interrogated in primary cardiac fibroblasts using a TGF-? reporter assay. Sufficiency was tested with a fibrillin-1?binding module of LTBP2 delivered as purified protein or by lentiviral expression. LTBP2 was induced in injury-activated cardiac fibroblasts and localized to infarct and remote myocardium by 7 days post-MI. Ltbp2 deletion improved 28-day survival (P=0.0272) where Ltbp2-null hearts showed preserved ejection fraction and faster diastolic strain rates, with protection concentrated in segments remote from the infarct. Remote myocardium contained less interstitial collagen and was significantly less stiff. Proteomic profiling showed enrichment of ECM organization and TGF-??responsive programs in wild-type hearts that was attenuated in knockouts. In fibroblasts, loss of LTBP2 increased LTBP1 matrix incorporation and shifted TGF-? from the soluble to the matrix-bound compartment; conversely, the minimal LTBP2 module bound fibrillin-1 directly and mobilized latent TGF-? from established matrix within 20 minutes. LTBP2 drives maladaptive remodeling of remote myocardium after MI by limiting matrix sequestration of latent TGF-? and expanding the activatable pool, resolving how an LTBP that does not bind latent TGF-? amplifies TGF-??dependent fibrosis. LTBP2 and its fibrillin-1 interaction surface may be tractable targets.
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BibTeX
@misc{ehsan2026latent,
title = {{Latent Transforming Growth Factor Binding Protein ? 2 promotes microfibrillar TGF-? bioavailability to drive pathologic fibrosis in remote regions of infarcted hearts}},
author = {F. Ehsan and M. Di Paola and M. Dewar and H. Zhang and U. Kuzmanov and Y.-Q. Zhou and C. J. Reitz and H. Shah and T. Wang and J. Liu and A. Izumi and R. Hu and J. Hendy and F. S. Younesi and M. K. Friedberg and F. Billia and T. Nakamura and B. Hinz and R. P. Mecham and A. O. Gramolini and S. P. Heximer},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.762676},
url = {https://www.biorxiv.org/content/10.64898/2026.10.28.762676v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Latent Transforming Growth Factor Binding Protein ? 2 promotes microfibrillar TGF-? bioavailability to drive pathologic fibrosis in remote regions of infarcted hearts
AU - F. Ehsan
AU - M. Di Paola
AU - M. Dewar
AU - H. Zhang
AU - U. Kuzmanov
AU - Y.-Q. Zhou
AU - C. J. Reitz
AU - H. Shah
AU - T. Wang
AU - J. Liu
AU - A. Izumi
AU - R. Hu
AU - J. Hendy
AU - F. S. Younesi
AU - M. K. Friedberg
AU - F. Billia
AU - T. Nakamura
AU - B. Hinz
AU - R. P. Mecham
AU - A. O. Gramolini
AU - S. P. Heximer
PY - 2026
DA - 2026/10/28
PB - bioRxiv
DO - 10.64898/2026.10.28.762676
UR - https://www.biorxiv.org/content/10.64898/2026.10.28.762676v1
AB - Myocardial infarction (MI) initiates ventricular remodeling that extends beyond the infarct into remote, viable myocardium, where diffuse extracellular matrix (ECM) remodeling and stiffening contribute to progressive dysfunction and heart failure. Latent transforming growth factor binding protein 2 (LTBP2) is an injury-induced, microfibril-associated ECM glycoprotein that, among the LTBP family, does not covalently bind latent TGF-?. We asked whether LTBP2 regulates remote remodeling after MI, and how a protein lacking latent TGF-??binding capacity could influence TGF-??dependent fibrosis. Wild-type and Ltbp2-null mice underwent permanent coronary ligation or sham surgery and were followed for 28 days by echocardiography and speckle-tracking strain analysis. Remote myocardium was assessed by histology, atomic force microscopy, and quantitative proteomics. Mechanism was interrogated in primary cardiac fibroblasts using a TGF-? reporter assay. Sufficiency was tested with a fibrillin-1?binding module of LTBP2 delivered as purified protein or by lentiviral expression. LTBP2 was induced in injury-activated cardiac fibroblasts and localized to infarct and remote myocardium by 7 days post-MI. Ltbp2 deletion improved 28-day survival (P=0.0272) where Ltbp2-null hearts showed preserved ejection fraction and faster diastolic strain rates, with protection concentrated in segments remote from the infarct. Remote myocardium contained less interstitial collagen and was significantly less stiff. Proteomic profiling showed enrichment of ECM organization and TGF-??responsive programs in wild-type hearts that was attenuated in knockouts. In fibroblasts, loss of LTBP2 increased LTBP1 matrix incorporation and shifted TGF-? from the soluble to the matrix-bound compartment; conversely, the minimal LTBP2 module bound fibrillin-1 directly and mobilized latent TGF-? from established matrix within 20 minutes. LTBP2 drives maladaptive remodeling of remote myocardium after MI by limiting matrix sequestration of latent TGF-? and expanding the activatable pool, resolving how an LTBP that does not bind latent TGF-? amplifies TGF-??dependent fibrosis. LTBP2 and its fibrillin-1 interaction surface may be tractable targets.
ER -