YAP1-mediated dysregulation of ACE-ACE2 activity augments cardiac fibrosis upon induction of hyperglycemic stress

• Published in: Biochimica et biophysica acta. General subjects Vol. 1868; no. 9; p. 130666
• Main Authors: Mondal, Arunima, Das, Shreya, Das, Madhuchhanda, Chakraborty, Santanu, Sengupta, Arunima
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2024
• Subjects: ACE; ACE2; Adaptor Proteins, Signal Transducing - metabolism; angiotensin II; Angiotensin-Converting Enzyme 2 - metabolism; Animals; beta Catenin - metabolism; Cardiac fibrosis; Cardiomegaly - metabolism; Cardiomegaly - pathology; cardiomyocytes; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; fibroblasts; fibrosis; Fibrosis - metabolism; gene expression regulation; glucose; hyperglycemia; Hyperglycemia - metabolism; Hyperglycemia - pathology; hypertrophy; Male; Mice; Mice, Inbred C57BL; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Peptidyl-Dipeptidase A - metabolism; protein synthesis; renin; Renin-Angiotensin System; RNA; Signal Transduction; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transforming Growth Factor beta1 - metabolism; Western blotting; YAP-Signaling Proteins - metabolism; YAP1; YAP1; Cardiac fibrosis; ACE2; ACE; RAS; NG; VP; Diabetes; EMT; HG
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2024.130666

Diabetic stress acts on the cardiac tissue to induce cardiac hypertrophy and fibrosis. Diabetes induced activated renin angiotensin system (RAS) has been reported to play a critical role in mediating cardiac hypertrophy and fibrosis. Angiotensin converting enzyme (ACE) in producing Angiotensin-II, promotes cardiomyocyte hypertrophy and fibrotic damage. ACE2, a recently discovered molecule structurally homologous to ACE, has been reported to be beneficial in reducing the effect of RAS driven pathologies. In vivo diabetic mouse model was used and co-labelling immunostaining assay have been performed to analyse the fibrotic remodeling and involvement of associated target signaling molecules in mouse heart tissue. For in vitro analyses, qPCR and western blot experiments were performed in different groups for RNA and protein expression analyses. Fibrosis markers were observed to be upregulated in the diabetic mouse heart tissue as well as in high glucose treated fibroblast and cardiomyocyte cells. Hyperglycemia induced overexpression of YAP1 leads to increased expression of β-catenin (CTNNB1) and ACE with downregulated ACE2 expression. The differential expression of ACE/ACE2 promotes TGFB1-SMAD2/3 pathway in the hyperglycemic cardiomyocyte and fibroblast resulting in increased cardiac fibrotic remodeling. In the following study, we have reported YAP1 modulates the RAS signaling pathway by inducing ACE and inhibiting ACE2 activity to augment cardiomyocyte hypertrophy and fibrosis in hyperglycemic condition. Furthermore, we have shown that hyperglycemia induced dysregulation of ACE-ACE2 activity by YAP1 promotes cardiac fibrosis through β-catenin/TGFB1 dependent pathway. •Diabetes stress in cardiac tissue results in alteration in cellular architecture and promotes cardiac fibrotic remodeling.•Hyperglycemia activates YAP1 and β-catenin activity leading to cardiac fibrosis through TGF-β/SMAD2/3 pathway.•Hyperglycemia induced dysregulation of ACE-ACE2 activity by YAP/β-catenin signaling promotes cardiac fibrotic remodeling.•ACE2 proves to be a key protective molecule in ameliorating hyperglycemic stress induced fibrotic remodeling in adult heart.