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

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 Ca 2+ uptake and SR Ca 2+ 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 Ca 2+ 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 Ca 2+ 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.

In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure

“…This is further confirmed by no change in SERCA-2a/PLB ratio between sham and ACF. These findings are in contrary with those of Juric et al 18] who found unaltered SERCA levels but reduced phosphorylation levels of PLB after 28 wks of ACF induction in rats. However, these discrepancies might be attributed to the difference in shunt size and therefore a dissimilar temporal progression of HF.…”

“…However, these discrepancies might be attributed to the difference in shunt size and therefore a dissimilar temporal progression of HF. Our lab, along with several others, observed an increased Ser-2808 phosphorylation of RyR relating to increased SR [Ca 2+ ] i leak in ACF myocytes [18–20]. Contrary to this, Juric et al observed an increase in the protein levels of FKBP 12.6 that is thought to stabilize RyR in its conformation.…”

“…Much less is known about the molecular and cellular mechanisms that underlie VO-induced HF. Our lab and others, using the aorto-caval fistula (ACF) rat model, have reported progressive LV pump failure associated with decreased myocyte contractility [3, 4]. …”

Regulation of L-type inward calcium channel activity by captopril and angiotensin II via the phosphatidyl inositol 3-kinase pathway in cardiomyocytes from volume-overload hypertrophied rat hearts

“…Cardiac hypertrophy is the compensatory enlargement of the heart aimed at reducing stress induced by volume overload (VO) (Juric et al 2010). Arteriovenous shunt or fistula has long been used as a model for inducing volume overload similar to that seen in conditions such as mitral valve regurgitation, aortic insufficiency, renal failure, obesity, hyperthyroidism, anemia, and bundle branch block (Wang et al 2003).…”

In vitro studies of early cardiac remodeling impact on contraction and calcium handling

“…Work done in rats treated to induce a volume overload model of cardiac hypertrophy showed increased diastolic function, impaired systolic function, and increased RyR binding protein FKBP12.6 phosphorylation. This suggested that, in this particular model, RyR played an important role in the maintenance of systolic function (26). Fluctuations in the phosphorylation and activation of these channels also lead to changes in calcium flux.…”