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Protein Kinase G I (PKGI) has been implicated as a negative regulator of pathologic cardiac hypertrophy [1,2], though the specific molecular mechanisms involved are unknown. To test the hypothesis that PKGIα negatively regulates cardiac hypertrophy, we characterized the cardiac phenotype in mice homozygous for a leucine zipper mutant (LZM) form of PKGIα in which critical amino acids in the N-terminal LZ motif have been substituted to disrupt PKGIα LZ binding to specific downstream effector proteins. We characterized the hearts of these LZM mice morphologically, by echocardiography and invasive hemodynamics in the unstressed state, and following pressure overload-induced cardiac hypertrophy. In the unstressed state, male PKG Iα LZM mice develop progressive left ventricular hypertrophy (LV mass/ tibia length) compared with wild type (WT) littermates with LV mass 12.3% greater at 30 weeks of age (p = 0.05, n = 10 WT, 9 LZM); and 27% greater at 60 weeks of age (p < 0.001, n = 5 WT, 13 LZM). Compared with age matched WT mice, the hearts of 30 week old PKGIα mutants are hypercontractile with decreased end systolic diameter (2.25 mm WT vs 1.95 mm LZM, p = 0.02) and increased fractional shortening (36.9% WT vs 42.2% LZM, p = 0.03) on echocardiography (n = 9 wt, 9 LZM). Invasive hemodynamic assessment demonstrates that LZM mice also have increased left ventricular systolic pressure (107.0 mmHg WT vs 120.7 mmHg LZM, p = 0.04), developed pressure (107.5 mmHg WT vs 119.2 mmHg LZM, p = 0.05), and LV dP/dt max (8972 mmHg/s WT vs 9802 mmHg/s LZM, p = 0.13).

In vivo evidence that cyclic GMP-dependent protein kinase G type I α mediates an anti-hypertrophic pathway in the heart