GSK-3ß heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy.

ABSTRACT

Glycogen synthase kinase-3ß (GSK-3ß) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3ß in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3ß (GSK-3ß(+/-) KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3ß(+/-) KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3ß(+/-) KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac ß-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3ß(+/-) KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3ß is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.