Engineered cardiac tissues:a novel in vitro model to investigate the pathophysiology of mouse diabetic cardiomyopathy

• 作者: Xiang Wang Xin-xin Chen Hai-tao Yu Yi Tan Qian Lin Bradley B.Keller Yang Zheng Lu Cai
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Cardiovascular Pharmacology
• 页码范围: 932-941
• 页数: 10页
• 语种: 英文

摘要

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.