L-GILZ is essential for cardiac function and protects against pressure overload-induced hypertrophy and dysfunction in mice.

Objective: 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. Methods: 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. Results: 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. Conclusion: 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.