Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.

OBJECTIVES Mechanical overload can be classified into pressure overload and volume overload, causing concentric and eccentric cardiac hypertrophy, respectively. Here, we aimed to differentiate the load-mediated signaling pathways involved in pressure versus volume overload cardiac hypertrophy. METHODS Pressure or volume overload was imposed on C57BL/6J mice by transverse aortic constriction (TAC), or aortic regurgitation (AR), respectively. Two weeks after surgery, left ventricular structure and function were evaluated by echocardiographic, hemodynamic and histological analyses. Signaling pathways related to hypertrophy, fibrosis, angiogenesis and apoptosis were studied by histological analysis, RT-PCR and Western blotting. RESULTS Although mean wall stress was similar in both TAC and AR mice, systolic wall stress was significantly increased in TAC, and diastolic wall stress was mainly elevated in AR. TAC or AR induced concentric or eccentric compensated hypertrophy, respectively. TAC was associated with more significant fibrosis and apoptosis, whereas AR was associated with more significant angiogenesis. The MAPK kinase family, β-arrestin-2, Akt and calcium-related signaling pathways were markedly activated in TAC but mildly up-regulated or unchanged in AR. CONCLUSIONS Pressure overload and volume overload induce different phenotypic and molecular adaptations in cardiac hypertrophy. Most load-related signaling pathways assessed in this study predominate in pressure but not volume overload. The stimulus-specific heterogeneity in the signaling pathways requires distinct manipulations for further mechanistic and pharmacological studies.