Defects in ryanodine receptor function are associated with systolic dysfunction in rats subjected to volume overload

Citation

Juric, D., Yao, X.-H., Thandapilly, S.J., Louis, X.L., Cantor, E.J.F., Chaze, B., Wojciechowski, P., Vasanji, Z., Yang, T., Wigle, J., and Netticadan, T. (2010). "Defects in ryanodine receptor are associated with systolic dysfunction in rats subjected to volume overload.", Experimental Physiology, 95(8), pp. 869-879. doi : 10.1113/expphysiol.2009.052100

Abstract

Cardiac hypertrophy is the compensatory enlargement of the heart aimed at reducing stress induced by either pressure overload or volume overload (VO); however, sustained hypertrophy leads to cardiac dysfunction. We hypothesize that cardiac dysfunction which develops due to VO will be associated with abnormalities in sarcoplasmic reticulum (SR) function. Volume overload was induced in rats by aortocaval shunt surgery ('VO rats'). Echocardiographic measurements were used to compare cardiac structure and function in control and VO rats. The SR was isolated from left ventricular tissue. Sarcoplasmic reticulum Ca2+ uptake and SR Ca2+ release were examined by the filtration method. The expression levels of SR proteins were assessed by Western immunoblotting. Rats subjected to VO developed eccentric hypertrophy. Diastolic function in VO rats was improved at all time points and was associated with elevated SR Ca2+ uptake at 16 and 28 weeks. Sarcoendoplasmic reticulum ATPase 2a protein level was increased at 16 weeks but normalized at 28 weeks; Amounts of phospholamban protein were unaltered, but Serine16 phospholamban and Threonine17 phospholamban were reduced at 28 weeks. Systolic function was impaired in the VO rats at 16 and 28 weeks and was associated with reduced Ca2+ release at the 28 week time point. The ryanodine receptor 2 (RyR2) protein level was reduced at 28 weeks; RyR2 phosphorylation status and the amount of FK-binding protein 12.6 were increased at 28 weeks. On the basis of the results, we conclude that the progression of hypertrophy due to VO in rats is accompanied by the impairment of systolic function, which in turn is associated with defects in RyR2 expression and function. © 2010 The Physiological Society.