Sestrin2 protects against pressure overload–induced pathological cardiac hypertrophy via ULK1
T Liu, Q DaiAbstract
Background
Pathological cardiac hypertrophy (PCH) is a major reason for heart failure and is associated with increased mortality. Unc-51-like kinase 1 (ULK1) is a key regulator of autophagy initiation, processes that are importantly involved in PCH. Sestrin2 is a stress-inducible protein implicated in metabolic homeostasis and cardioprotection.
Purpose
The present study aimed to investigate the function of Sestrin2 in transverse aortic constriction (TAC)-induced PCH and possible mechanisms.
Methods
Eight-week-old male C57BL/6 mice were injected with cardiac-specific Sestrin2 overexpression (AAV9-Sestrin2) to achieve cardiac-specific overexpression. Two weeks after viral injection, mice underwent TAC. Cardiac structure and function were evaluated by echocardiography and heart weight index six weeks after TAC. Masson and wheat germ agglutinin (WGA) staining were used to assess myocardial interstitial fibrosis and cardiomyocyte cross-sectional area. IP-Western analysis was performed to identify the Sestrin2-ULK1 interaction.
Results
TAC downregulated Sestrin2 expression (Fig. 1A), concomitant with a significant increase in the heart weight-to-body weight ratio compared with sham-operated mice (Fig. 1E-F), which was markedly reduced by Sestrin2 overexpression. Functional assessment revealed that TAC resulted in a pronounced increase in left ventricular interventricular septal thickness, accompanied by impaired diastolic and systolic function; these structural and functional abnormalities were substantially ameliorated in Sestrin2-overexpressing mice (Fig. 1B-D). Histological analyses further indicated that Sestrin2 overexpression significantly attenuated myocardial interstitial fibrosis and reduced cardiomyocyte cross-sectional area compared with TAC mice (Fig. 1G-J). Moreover, PCH-associated genes, including Anp, Bnp, and Myh7, were markedly upregulated in TAC mice, an effect that was significantly blunted by Sestrin2 overexpression (Fig. 1K-M). Additionally, inhibition of ULK1 in myocardial tissue further exacerbated PCH. Computer simulations and IP-Western results indicated that Sestrin2 and ULK1 bind to and maintain the latter high expression in response to pressure overload conditions (Fig. 2A-E).
Conclusion
Sestrin2 interacts with ULK1 and suppresses the progression of pathological cardiac hypertrophy. Sestrin2 may be a novel target for the prevention and treatment of pressure overload-associated cardiac hypertrophy.Fig. 1Fig. 2