Mechanistic basis of differences in Ca²⁺-handling properties of sarcoplasmic reticulum in right and left ventricles of normal rat myocardium

Abstract

transients, evoked by electrical field stimulation, were significantly prolonged in RV myocytes compared with LV myocytes, mainly because of slow decay of intracellular Ca 2ϩ concentration. The slow decay of intracellular Ca 2ϩ concentration in RV and consequent decrease in the speed of RV relaxation may promote temporal synchrony of the end of diastole in RV and LV. The preponderance of functionally silent SR Ca 2ϩ pumps in RV reflects a higher diastolic reserve required to protect and maintain RV function in the face of a sudden rise in afterload or resistance in the pulmonary circulation.calcium-adenosinetriphosphatase; phospholamban; phosphoenzyme; calcium transient; diastolic reserve THE OVERALL EFFECTIVENESS of the heart as a pump is greatly influenced by the interdependence of right ventricular (RV) and left ventricular (LV) function. LV and RV output is primarily determined by the interaction between ventricular preload, the contractile state of the myocardium, and the afterload encountered by the ventricle (16). However, the physiology and hemodynamic functions of RV in the normal state differ considerably from those of LV. For example, afterload, a major determinant of ventricular function, differs nearly sixfold between RV and LV under normal conditions (7).Cardiac adaptation to a variety of physiological stresses is inevitably linked to molecular remodeling of the sarcoplasmic reticulum (SR) Ca 2ϩ -cycling apparatus. The major Ca 2ϩ -cycling proteins in SR include the ryanodine receptor (RyR) Ca 2ϩ release channel (CRC), which is responsible for Ca 2ϩ release into cytosol on myocyte excitation to induce muscle contraction (5); sarco-(endo)plasmic Ca 2ϩ -ATPase (SERCA2a), which actively sequesters Ca 2ϩ back into SR lumen to promote muscle relaxation (18); the Ca 2ϩ -storage protein calsequestrin (27); and phospholamban (PLN), which regulates Ca 2ϩ -ATPase function (23,34,37). In its unphosphorylated state, PLN is thought to interact with Ca 2ϩ -ATPase, exerting an inhibitory effect manifested largely through a decrease in the enzyme's affinity for Ca 2ϩ ; phosphorylation of PLN by cAMP-dependent protein kinase or calmodulin (CaM) kinase is thought to disrupt this interaction, resulting in enhanced affinity of the ATPase for Ca 2ϩ and stimulation of Ca 2ϩ pump activity (23,34,37). This long-standing view has been questioned recently, and it has been reported that Ca 2ϩ , but not phosphorylation of PLN, disrupts the interaction between Ca 2ϩ -ATPase and PLN (1). Besides PLN, CaM and CaM kinase are tightly associated with cardiac SR and have been implicated in modulation of Ca 2ϩ uptake and release functions of SR through direct phosphorylation of Ca 2ϩ -ATPase (15,31,32,(43)(44)(45)(46) and RyR CRC (14,38,42).Increase in afterload of the systemic circulation is known to invoke tissue remodeling and altered Ca 2ϩ homeostasis in LV. However, the impact of physiological load of RV on SR function, to our knowledge, has not been studied. As a first step in exploring the mechanisms of RV adaptation to stress...

Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

“…28 SERCA2a and PLB mRNA levels were also similar in both ventricles in rats, 33 whereas protein expression of both was lower in RV. 26 In accordance, SR Ca 2+ sequestration was slower in RV compared with LV in normal rat myocardium, 38,26 There are few data available about chamber-specific Ca 2+ -handling properties in large mammals. RyR2 mRNA and protein expression were lower in RV compared with LV in myocardium of control dogs.…”

“…6 Potential ionic differences between basal LV and RV cellular electrophysiology have been identified at the mRNA, protein and functional levels (see Table 1). In most species and experimental models, the RV myocardium shows a relative overexpression of K v 4.2, K v 4.3 and KChIP2, 23,24 molecular components of I to , as well as greater KCNQ1 expression, 25,26 part of the I Ks macromolecular complex. In agreement, a number of studies observed larger I Ks and I to in RV compared with LV.…”

Molecular and physiological characterization of RV remodeling in a murine model of pulmonary stenosis

“…In the past, it was believed that differences in global structure and loading conditions represented the main differences between the right and left ventricles. However, recent work has shown an increasing divergence in the anterior and primary heart field pathways leading to the differentiation of RV versus LV cardiomyocytes during early development (46) and chamber-specific differences in cell signaling and calcium handling, suggesting fundamental differences between the right and left ventricles at the cellular level as well (10,32,34,54,72). Recent studies suggest that standard pharmacotherapies used to treat LV dysfunction may not be as effective in patients with dysfunction of a systemic right ventricle (18).…”

Regulation of sarcoplasmic reticulum Ca2+reuptake in porcine airway smooth muscle

“…SR membrane vesicles were isolated from ASM according to previously described procedures (18,53). Briefly, the smooth muscle layer from fresh porcine trachea was minced well on ice and suspended in ice-cold 10 mM NaHCO 3 buffer (pH 6.8) prepared in Ca 2ϩ -free water, 20 g/l leupeptin, and 100 g/l trypsin inhibitor.…”

“…Values were calculated as percent inhibition at each time point. The protein content of each aliquot was then determined to further normalize the actual 45 Ca 2ϩ uptake in nanomoles per milligram of protein (18,53,67).…”