Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy.
Increased cardiovascular mortality occurs in diabetic patients with or without coronary artery disease and is attributed to the presence of diabetic cardiomyopathy. One potential mechanism is hyperglycemia that has been reported to activate protein kinase C (PKC), preferentially the beta isoform, which has been associated with the development of micro- and macrovascular pathologies in diabetes mellitus. To establish that the activation of the PKCbeta isoform can cause cardiac dysfunctions, we have established lines of transgenic mice with the specific overexpression of PKCbeta2 isoform in the myocardium. These mice overexpressed the PKCbeta2 isoform transgene by 2- to 10-fold as measured by mRNA, and proteins exhibited left ventricular hypertrophy, cardiac myocyte necrosis, multifocal fibrosis, and decreased left ventricular performance without vascular lesions. The severity of the phenotypes exhibited gene dose-dependence. Up-regulation of mRNAs for fetal type myosin heavy chain, atrial natriuretic factor, c-fos, transforming growth factor, and collagens was also observed. Moreover, treatment with a PKCbeta-specific inhibitor resulted in functional and histological improvement. These findings have firmly established that the activation of the PKCbeta2 isoform can cause specific cardiac cellular and functional changes leading to cardiomyopathy of diabetic or nondiabetic etiology.
Wakasaki
H
H
Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
Koya
D
D
Schoen
F J
FJ
Jirousek
M R
MR
Ways
D K
DK
Hoit
B D
BD
Walsh
R A
RA
King
G L
GL
D000818:Animals; D001483:Base Sequence; D009202:Cardiomyopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics*
D011493:Protein Kinase C