L-GILZは心機能に不可欠であり、マウスにおける圧力過負荷誘発性肥大および機能不全から保護する

Glucocorticoid-induced leucine zipper (GILZ) deficiency has been shown to exacerbate angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction. However, the specific role of the long isoform of GILZ (L-GILZ) in cardiac function remains unclear. This study aimed to investigate the role of L-GILZ in maintaining cardiac function and its protective effects against pressure overload-induced hypertrophy and dysfunction.

Institute of Cancer Research mice were used in this study. The human L-GILZ gene or short hairpin RNA targeting mouse L-GILZ was introduced via adeno-associated virus 9 under the control of the cardiac troponin-T promoter, ensuring cardiac-specific overexpression or knockdown. Luciferase and short hairpin RNA targeting LacZ served as respective controls. L-GILZ expression was analyzed by western blot analysis and real-time polymerase chain reaction, while extracellular signal-regulated kinase (ERK) phosphorylation was assessed via western blot analysis. RNA sequencing was performed to evaluate gene expression changes following L-GILZ knockdown. Pressure overload was induced by transverse aortic constriction (TAC), and echocardiography was used to assess cardiac function.

TAC-induced pressure overload reduced L-GILZ expression but not GILZ expression. Cardiac-specific overexpression of human L-GILZ was successfully achieved in mouse hearts, with no detectable expression in other organs. L-GILZ overexpression significantly attenuated TAC-induced cardiac hypertrophy, dysfunction, and ERK phosphorylation. Conversely, L-GILZ knockdown led to hypertrophy, cardiac dysfunction, and enhanced ERK phosphorylation. RNA sequencing revealed that L-GILZ knockdown reduced the expression of mitochondria-associated genes, including cytochrome c oxidase, adenosine triphosphate synthase, and mitochondrial nicotinamide adenine dinucleotide (reduced form) dehydrogenase.

L-GILZ plays a critical role in maintaining cardiac function and homeostasis. Cardiac-specific overexpression of L-GILZ may serve as a potential therapeutic strategy for preventing and treating cardiac hypertrophy and heart failure.