1. Academic Validation
  2. LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling

LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling

  • Biochim Biophys Acta Mol Basis Dis. 2018 Oct;1864(10):3322-3338. doi: 10.1016/j.bbadis.2018.07.019.
Lu Gao 1 Yuan Liu 1 Sen Guo 1 Lili Xiao 1 Leiming Wu 1 Zheng Wang 1 Cui Liang 1 Rui Yao 1 Yanzhou Zhang 2
Affiliations

Affiliations

  • 1 Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: yzzhang6@163.com.
Abstract

Diabetes contributes to cardiovascular complications and the pathogenesis of cardiac remodeling that can lead to heart failure. We aimed to evaluate the functional role of LAZ3 in diabetic cardiomyopathy (DCM). Streptozotocin (STZ) was used to induce a diabetic mouse model. Three months after induction, the mice were subjected to retro-orbital venous plexus injection of adeno-associated virus 9 (AAV9) that overexpressed LAZ3. Six weeks after the Infection, mouse hearts were removed to assess the degree of cardiac remodeling. LAZ3 was down-regulated in the diabetic mouse hearts and high glucose stimulated cardiomyocytes. Knock-down of LAZ3 in cardiomyocytes with LAZ3 siRNA reduced cell viability, increased the inflammatory response and induced oxidative stress and cell Apoptosis. Overexpression of LAZ3 by Infection with adeno-associated virus (AAV9)-LAZ3 protected against an inflammatory response, oxidative stress and cell Apoptosis in both a high glucose stimulated in vitro study and diabetic mouse hearts. We found that LAZ3 increased the activation of PPARa, which increased PGC-1a activation and subsequently augmented NRF2 expression and nuclear translocation. This outcome was confirmed by NRF2 siRNA and a PPARa activator, since NRF2 siRNA abrogated the protective effects of LAZ3 overexpression, while the PPARa activator reversed the deteriorating phenotype of LAZ3 knock-down in both the in vitro and vivo study. Furthermore, LAZ3 decreased miR-21 expression, which resulted in PPARa activation, NRF2 expression and nuclear translocation. In conclusion, LAZ3 protects against cardiac remodeling in DCM by decreasing miR-21, thus regulating PPARa/NRF2 signaling.

Keywords

Cardiac remodeling; Diabetes; LAZ3; PPARa; miR-21.

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