Nε-Carboxymethyl-Lysine Modification of Extracellular Matrix Proteins Augments Fibroblast Activation

• Published in: International journal of molecular sciences Vol. 24; no. 21; p. 15811
• Main Authors: Ediga, Harshavardhana H, Hester, Patrick, Yepuri, Adithi, Reddy, Geereddy Bhanuprakash, Madala, Satish K
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-11-2023
• Subjects: advanced glycation end products; Age; Aging; Antibodies; Apoptosis; Collagen; Diabetes; Enzymes; Ethylenediaminetetraacetic acid; Extracellular matrix; Fibroblasts; Gene expression; Homeostasis; idiopathic pulmonary fibrosis; Kinases; Lung diseases; Lungs; Lysine; myofibroblast transformation; Nε-carboxymethyl-lysine; Proteins; Pulmonary fibrosis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242115811

The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases.