L-GILZ is essential for cardiac function and protects against pressure
overload-induced hypertrophy and dysfunction in mice
#MMPMID41384037
Fu HY
; Imazu M
; Ito S
; Tsukamoto O
; Kitakaze M
Asian Heart J
2025[Jun]; 1
(1
): 44-52
PMID41384037
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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.
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