Abstract 104: Protein Kinase GIα Functions in the Cardiac Myocyte as a Tonic Inhibitor of Pathologic Cardiac Hypertrophy In Vivo
Objectives: We and others previously demonstrated that activation of the NO-cGMP-Protein Kinase G (PKG) pathway inhibits cardiac hypertrophy and remodeling in vivo. However, it remains untested whether PKG specifically in the cardiac myocyte (CM) mediates these effects. We therefore tested the hypothesis that PKGIα inhibits pathologic cardiac hypertrophy through a specific role in the CM.
Methods and Results: We created and characterized mice with CM-restricted excision of PKGIα. Mice were generated in which the PKGI exon 1 (specific for the Iα isoform) was flanked by loxP sites. We crossed these PKGIαfl/fl mice with αMHC-Cre mice which constitutively express Cre recombinase selectively in the CM. The resultant PKGIαfl/fl/ αMHC-Cre+/- mice were compared with PKGIαfl/fl/ αMHC-Cre-/- littermate controls (termed PKGCMKO and Ctrl, respectively). By age 3 months (n=5 per genotype), male PKGCMKO mice developed atrial and LV hypertrophy compared with Ctrl littermates PKGCMKO atrial weight/tibia length 0.33 ± 0.03 mg/mm vs 0.22 ± .01 in Ctrl, P<0.05; PKGCMKO LV/TL 5.0 ± 0.2 mg/mm vs 4.1 ± 0.4 in Ctrl, P <0.05). LV CM cross sectional area also increased in the 3 month old PKGCMKO mice (9445 ± 282 pixels PKGCMKO vs 8273 ± 213 in Ctrl, n>400 cells/genotype, 5 hearts per genotype; P<0.001). The systolic index end systolic elastance was decreased in 3 month old PKGCMKO mice (PKGCMKO 3.1 ± 0.4 mmHg/μ l vs 6.1 ± 1.0 in Ctrl-; P<0.05). Importantly, blood pressure did not differ between genotypes. By age 6 months, PKGCMKO mice developed early mortality (3 of 4 PKGCMKO males died at 6 months of age vs 0 of 4 Ctrl males). Total heart and atrial weights of male mice (n=3 PKGCMKO, 4 Ctrl) increased in PKGCMKO mice (heart weight/tibia length 10.8 ± 1.7 mg/mm in PKGCMKO vs 7.1 ± 0.6 in Ctrl; P<0.05; atrial weight/tibia length 2.3 ± 1.1 mg/mm in PKGCMKO vs 0.30 ± 0.1 Ctrl, P<0.05). LV fractional shortening percentage, recorded at 6 months age, trended lower in the PKGCMKO mice as well (35 ± 3% PKGCMKO vs 44 ± 4% Ctrl, P 0.09).
Conclusions: These data provide the first evidence that PKGIα functions in the CM as a tonic inhibitor of age-dependent pathologic hypertrophy, supporting further study of PKGIα as a therapeutic target in the prevention and treatment of LV remodeling and congestive heart failure.
- © 2012 by American Heart Association, Inc.