Cardiac metallothionein overexpression rescues diabetic cardiomyopathy in Akt2-knockout mice.

Abstract

To efficiently prevent diabetic cardiomyopathy (DCM), we have explored and confirmed that metallothionein (MT) prevents DCM by attenuating oxidative stress, and increasing expression of proteins associated with glucose metabolism. To determine whether Akt2 expression is critical to MT prevention of DCM, mice with either global Akt2 gene deletion (Akt2‐KO), or cardiomyocyte‐specific overexpressing MT gene (MT‐TG) or both combined (MT‐TG/Akt2‐KO) were used. Akt2‐KO mice exhibited symptoms of DCM (cardiac remodelling and dysfunction), and reduced expression of glycogen and glucose metabolism‐related proteins, despite an increase in total Akt (t‐Akt) phosphorylation. Cardiac MT overexpression in MT‐TG/Akt2‐KO mice prevented DCM and restored glucose metabolism‐related proteins expression and baseline t‐Akt phosphorylation. Furthermore, phosphorylation of ERK1/2 increased in the heart of MT‐TG/Akt2‐KO mice, compared with Akt2‐KO mice. As ERK1/2 has been implicated in the regulation of glucose transport and metabolism this increase could potentially underlie MT protective effect in MT‐TG/Akt2‐KO mice. Therefore, these results show that although our previous work has shown that MT preserving Akt2 activity is sufficient to prevent DCM, in the absence of Akt2 MT may stimulate alternative or downstream pathways protecting from DCM in a type 2 model of diabetes, and that this protection may be associated with the ERK activation pathway.