BACKGROUND: Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin. METHODS AND RESULTS: We showed that calcineurin enzymatic activity is increased 3. 2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy. CONCLUSIONS: These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.
BACKGROUND: Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin. METHODS AND RESULTS: We showed that calcineurin enzymatic activity is increased 3. 2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy. CONCLUSIONS: These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.
Authors: Orlando F Bueno; Benjamin J Wilkins; Kevin M Tymitz; Betty J Glascock; Thomas F Kimball; John N Lorenz; Jeffery D Molkentin Journal: Proc Natl Acad Sci U S A Date: 2002-03-19 Impact factor: 11.205
Authors: Shavonn C Smith; Xiaoxiao Zhang; Xiaoying Zhang; Polina Gross; Timothy Starosta; Sadia Mohsin; Michael Franti; Priyanka Gupta; David Hayes; Maria Myzithras; Julius Kahn; James Tanner; Steven M Weldon; Ashraf Khalil; Xinji Guo; Abdelkarim Sabri; Xiongwen Chen; Scott MacDonnell; Steven R Houser Journal: Circ Res Date: 2015-09-17 Impact factor: 17.367