Engineered cardiac tissues: a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy
| Autor: | Bradley B. Keller, Yang Zheng, Qian Lin, Hai-tao Yu, Xiang Wang, Yi Tan, Lu Cai, Xinxin Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Glycation End Products
Advanced 0301 basic medicine Diabetic Cardiomyopathies Receptor for Advanced Glycation End Products SOD2 Inflammation Caspase 3 Pharmacology medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Glycation Fibrosis Diabetic cardiomyopathy Animals Medicine Myocytes Cardiac Pharmacology (medical) Cells Cultured Tissue Engineering business.industry Myocardium General Medicine medicine.disease Acetylcysteine CTGF Oxidative Stress 030104 developmental biology 030220 oncology & carcinogenesis Benzamides medicine.symptom business Oxidative stress |
| Zdroj: | Acta Pharmacol Sin |
| ISSN: | 1745-7254 1671-4083 |
| Popis: | Rodent diabetic models, used to understand the pathophysiology of diabetic cardiomyopathy (DCM), remain several limitations. Engineered cardiac tissues (ECTs) have emerged as robust 3D in vitro models to investigate structure–function relationships as well as cardiac injury and repair. Advanced glycation end-products (AGEs), produced through glycation of proteins or lipids in response to hyperglycemia, are important pathogenic factor for the development of DCM. In the current study, we developed a murine-based ECT model to investigate cardiac injury produced by AGEs. We treated ECTs composed of neonatal murine cardiac cells with AGEs and observed AGE-related functional, cellular, and molecular alterations: (1) AGEs (150 µg/mL) did not cause acute cytotoxicity, which displayed as necrosis detected by medium LDH release or apoptosis detected by cleaved caspase 3 and TUNEL staining, but negatively impacted ECT function on treatment day 9; (2) AGEs treatment significantly increased the markers of fibrosis (TGF-β, α-SMA, Ctgf, Collagen I-α1, Collagen III-α1, and Fn1) and hypertrophy (Nppa and Myh7); (3) AGEs treatment significantly increased ECT oxidative stress markers (3-NT, 4-HNE, HO-1, CAT, and SOD2) and inflammation response markers (PAI-1, TNF-α, NF-κB, and ICAM-1); and (4) AGE-induced pathogenic responses were all attenuated by pre-application of AGE receptor antagonist FPS-ZM1 (20 µM) or the antioxidant glutathione precursor N-acetylcysteine (5 mM). Therefore, AGEs-treated murine ECTs recapitulate the key features of DCM’s functional, cellular and molecular pathogenesis, and may serve as a robust in vitro model to investigate cellular structure-function relationships, signaling pathways relevant to DCM and pharmaceutical intervention strategies. |
| Databáze: | OpenAIRE |
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