Abstract 20521: Disruption of Protein Kinase A Confers Resistance to Age and Angiotensin-Induced Cardiac Dysfunction
Protein kinase A (PKA) is a cAMP-activated enzyme consisting of multiple regulatory and catalytic subunits. The PKA pathway, which regulates numerous different physiological responses including metabolism, cell division, and heart contractility, has been implicated by a number of studies in aging and cardiac dysfunction. We have shown that mutations that cause a reduction in PKA signaling delay the incidence and severity of age-related disease in mice. Specifically, loss of the RIIβ regulatory subunit protects mice against age-related cardiac dysfunction. We were therefore interested to determine if disruption of the PKA Cβ catalytic subunit would also result in an age-resistant cardiac phenotype. We used echocardiography and doppler imaging to assess systolic and diastolic function in aging Cβ null mice and WT littermates. By 24 months of age, Cβ null mutants had higher left ventricular (LV) fractional shortening (FS) percentages compared to WT, (48% in mutants compared to 45% for WT, P=0.078). The mass performance index (MPI) of Cβ null mice was over 20% lower than WT littermates (P=0.012), reflecting shorter isovolumic contraction and relaxation times. The mutants also displayed 30% higher LV early to late filling ratios (Ea/Aa) compared to WT (P=0.0001) indicating superior diastolic function. WT mice had enlarged left atria, with aorta/left atrium (AO/LA) ratios 25% lower than those of mutants (P=0.0001), and increased left ventricular mass index (LVMI) (P=0.0005). At autopsy, WT mice had enlarged hearts that were 45% heavier in males and 25% heavier in females than littermates lacking PKA Cβ (P=0.003 and 0.024). These results in old mice were confirmed by challenging younger (7 month-old) mice with angiotensin (ang) II. It was found that while Cβ null mice were sensitive to the hypertensive effects of ang II, they were resistant to its detrimental effects on cardiac morphology and function. Cardiac function of angiotensin-treated PKA Cβ null mice was significantly superior to that of WT littermates for FS, Ea/Aa, AO/LA and LVMI. In conclusion, disruption of the PKA Cβ catalytic subunit confers resistance to both age and angiotensin-induced cardiac hypertrophy and dysfunction, suggesting a clinically relevant target for age-related heart disease.
- © 2010 by American Heart Association, Inc.