Extracellular matrix alterations in chronic ischemic cardiomyopathy revealed by quantitative proteomics
Kevin M. Buck, Holden T. Rogers, Zachery R. Gregorich, Morgan W. Mann, Timothy J. Aballo, Zhan Gao, Emily A. Chapman, Andrew J. Perciaccante, Scott J. Price, Ienglam Lei, Paul C. Tang, Ying Ge
Kevin M. Buck, Holden T. Rogers, Zachery R. Gregorich, Morgan W. Mann, Timothy J. Aballo, Zhan Gao, Emily A. Chapman, Andrew J. Perciaccante, Scott J. Price, Ienglam Lei, Paul C. Tang, Ying Ge
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Research Article Cardiology Genetics

Extracellular matrix alterations in chronic ischemic cardiomyopathy revealed by quantitative proteomics

Abstract

Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM-targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM and nonfailing donor hearts. High-resolution mass spectrometry–based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1, FBLN1, and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFB signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.

Authors

Kevin M. Buck, Holden T. Rogers, Zachery R. Gregorich, Morgan W. Mann, Timothy J. Aballo, Zhan Gao, Emily A. Chapman, Andrew J. Perciaccante, Scott J. Price, Ienglam Lei, Paul C. Tang, Ying Ge

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Figure 3

ECM remodeling in end-stage HF from ICM.

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ECM remodeling in end-stage HF from ICM. (A) Dot plot showing categorica...
(A) Dot plot showing categorical log2 fold change in the intensities of matrisome proteins. Mean and SD of log2 fold changes for all ECM proteins in each extract and category were plotted. Overall, core matrisome proteins (collagens, proteoglycans, and glycoproteins), as well as ECM regulators, were significantly upregulated in failing ICM LV tissue. Means were tested for significance using Student’s 2-tailed t test, and the 97.5% confidence interval was computed. (B) Volcano plot showing select proteins up- and downregulated in failing ICM versus nonfailing donor myocardium. To be considered significant, a log fold change > 0.6 (>1.5-fold) and an adjusted P < 0.05 (–log p-adj > 1.3) were both required. (C) Core collagens, ECM regulators, glycoproteins, and proteoglycans show increased expression in ICM. Box plots show the interquartile range, median (line), and minimum and maximum (whiskers). Significance testing was performed using limma. Then P values were adjusted by independent hypothesis weighting and plotted as follows: *** ≤ 0.001. (D) Clustered heatmap and corresponding bubble plots showing the results of GO analysis using the list of ECM proteins upregulated in failing ICM myocardial tissue. In the first cluster, biological processes (top) relate to carbohydrate metabolism with molecular functions (bottom) of binding and matrix structural properties. The second cluster pertains more to matrix regulation by growth factors and peptidases. FDR is P value–corrected by the Benjamini-Hochberg method, done automatically by STRING.