Enhanced Calcium Mobilization In Rat Ventricular Myocytes During The Onset Of Pressure Overload-induced Hypertrophy

Early cardiovascular changes evoked by pressure overload (PO) may reveal adaptive strategies that allow immediate survival to the increased hemodynamic load. In this study, systolic and diastolic Ca 2+ cycling was analyzed in left ventricular rat myocytes before (day 2, PO-2d group) and after (day 7, PO-7d group) development of hypertrophy subsequent to aortic constriction, as well as in myocytes from timematched sham-operated rats (sham group). Ca 2+ transient amplitude was significantly augmented in the PO-2d group. In the PO-7d group, intracellular Ca 2+ concentration ([Ca 2+] i) was reduced during diastole, and mechanical twitch relaxation (but not [Ca 2+] i decline) was slowed. In PO groups, fractional sarcoplasmic reticulum (SR) Ca 2+ release at a twitch, SR Ca 2+ content, SR Ca 2+ loss during diastole, and SR-dependent integrated Ca 2+ flux during twitch relaxation were significantly greater than in sham-operated groups, whereas the relaxation-associated Ca 2+ flux carried by the Na +/Ca 2+ exchanger was not significantly changed. In the PO-7d group, mRNA levels of cardiac isoforms of SR Ca 2+-ATPase (SERCA2a), phospholamban, calsequestrin, ryanodine receptor, and NCX were not significantly altered, but the SERCA2a-to-phospholamban ratio was increased 2.5-fold. Moreover, greater sensitivity to the inotropic effects of the β-adrenoceptor agonist isoproterenol was observed in the PO-7d group. The results indicate enhanced Ca 2+ cycling between SR and cytosol early after PO imposition, even before hypertrophy development. Increase in SR Ca 2+ uptake may contribute to enhancement of excitation-contraction coupling (augmented SR Ca 2+ content and release) and protection against arrhythmogenesis due to buildup of [Ca 2+] i during diastole. Copyright © 2006 the American Physiological Society.2914H1803H1813Akers, W.S., Cross, A., Speth, R., Dwoskin, L.P., Cassis, L.A., Reninangiotensin and sympathetic nervous system in cardiac pressure-overload hypertrophy (2000) Am J Physiol Heart Circ Physiol, 279, pp. H2797-H2806Anger, M., Lompré, A.M., Vallot, O., Marotte, F., Rappaport, L., Samuel, J.L., Cellular distribution of Ca 2+ pumps and Ca 2+ release channels in rat cardiac hypertrophy induced by aortic stenosis (1998) Circulation, 98, pp. 2477-2486Anversa, P., Ricci, R., Olivetti, G., Quantitative structural analysis of the myocardium during physiologic growth and induced cardiac hypertrophy (1986) J Am Coll Cardiol, 7, pp. 1140-1149Arai, M., Suzuki, T., Nagai, R., Sarcoplasmic reticulum genes are upregulated in mild cardiac hypertrophy but downregulated in severe cardiac hypertrophy induced by pressure overload (1996) J Mol Cell Cardiol, 28, pp. 1583-1590Bassani, J.W.M., Bassani, R.A., Bers, D.M., Twitch-dependent SR Ca accumulation and release in rabbit ventricular myocytes (1993) Am J Physiol Cell Physiol, 265, pp. C533-C540Bassani, J.W.M., Bassani, R.A., Bers, D.M., Relaxation in rabbit and rat cardiac cells: Species-dependent differences in cellular mechanisms (1994) J Physiol, 476, pp. 279-293Bassani, J.W.M., Yuan, W., Bers, D.M., Fractional SR Ca release is regulated by trigger Ca and SR Ca content in cardiac myocytes (1995) Am J Physiol Cell Physiol, 268, pp. C1313-C1319Bassani, R.A., Bassani, J.W.M., Contribution of Ca 2+ transporters to relaxation in intact ventricular myocytes from developing rats (2002) Am J Physiol Heart Circ Physiol, 282, pp. H2406-H2413Bassani, R.A., Bassani, J.W.M., Inhibition of the sarcoplasmic reticulum Ca 2+ pump with thapsigargin to estimate the contribution of Na +-Ca 2+ exchange to ventricular myocyte relaxation (2003) Braz J Med Biol Res, 36, pp. 1717-1723Bassani, R.A., Bassani, J.W.M., Lipsius, S.L., Bers, D.M., Diastolic Ca efflux in atrial pacemaker cells and Ca-overloaded myocytes (1997) Am J Physiol Heart Circ Physiol, 273, pp. H886-H892Bassani, R.A., Bers, D.M., Rate of diastolic Ca release from the sarcoplasmic reticulum of intact rabbit and rat ventricular myocytes (1995) Biophys J, 68, pp. 2015-2022Bassani, R.A., De Moraes, S., Effect of repeated footshock on the chronotropic responsiveness of the isolated pacemaker of the rat: Role of β 2-adrenoceptors (1988) J Pharmacol Exp Ther, 246, pp. 316-321Bassani, R.A., Shannon, T.R., Bers, D.M., Passive Ca 2+ binding in ventricular myocardium of neonatal and adult rats (1998) Cell Calcium, 23, pp. 433-442Bénitah, J.P., Kerfant, B.G., Vassort, G., Richard, S., Gómez, A.M., Altered communication between L-type calcium channels and ryanodine receptors in heart failure (2002) Front Biosci, 7, pp. E263-E275Berenji, K., Drazner, M.H., Rothermel, B.A., Hill, J.A., Does load-induced ventricular hypertrophy progress to systolic heart failure? (2005) Am J Physiol Heart Circ Physiol, 289, pp. H8-H16Bers, D.M., (2001) Excitation-Contraction Coupling and Cardiac Contractile Force (2nd Ed.), , Dordrecht, The Netherlands: Kluwer AcademicBidasee, K., Dinçer, D., Besch Jr., H.R., Ryanodine receptor dysfunction in hearts of streptozotocin-induced diabetic rats (2001) Mol Pharmacol, 60, pp. 1356-1364Brittsan, A.G., Kranias, E.G., Phospholamban and cardiac contractile function (2000) J Mol Cell Cardiol, 32, pp. 2131-2139Chorvatova, A., Hart, G., Hussain, M., Na +/Ca 2+ exchange current (I Na/Ca) and sarcoplasmic reticulum Ca 2+ release in catecholamine-induced cardiac hypertrophy (2004) Cardiovasc Res, 61, pp. 278-287Colomer, J.M., Mao, L., Rockman, H.A., Means, A.R., Pressure overload selectively upregulates Ca 2+/calmodulin- dependent protein kinase II in vivo (2003) Mol Endocrinol, 17, pp. 183-192Delbridge, L.M., Bassani, J.W.M., Bers, D.M., Steady-state Ca 2+ fluxes and cytosolic Ca 2+ buffering in rabbit ventricular myocytes (1996) Am J Physiol Cell Physiol, 270, pp. C192-C199Delbridge, L.M., Satoh, H., Yuan, W., Bassani, J.W.M., Qi, M., Ginsburg, K.S., Samarel, A.M., Bers, D.M., Cardiac myocyte volume, Ca 2+ fluxes, and sarcoplasmic reticulum loading in pressure-overload hypertrophy (1997) Am J Physiol Heart Circ Physiol, 272, pp. H2425-H2435Del Monte, F., Lebeche, D., Guerrero, J.L., Tsuji, T., Doyer, A.A., Gwathmey, J.K., Hajjar, R.J., Abrogation of ventricular arrhythmias in a model of ischemia and reperfusion by targeting myocardial calcium cycling (2004) Proc Natl Acad Sci USA, 101, pp. 5662-5627Dorn II, G.W., Robbins, J., Ball, N., Walsh, R.A., Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded rats (1994) Am J Physiol Heart Circ Physiol, 267, pp. H400-H405Dzimiri, N., Regulation of β-adrenoceptor signaling in cardiac function and disease (1999) Pharmacol Rev, 51, pp. 465-501Eckardt, L., Kirchof, P., Breithardt, G., Haverkamp, W., Load-induced changes in repolarization: Evidence from experimental and clinical data (2001) Basic Res Cardiol, 96, pp. 369-380Ganim, J.R., Luo, W., Ponniah, S., Grupp, I., Kim, H.W., Ferguson, D.G., Kadambi, V., Kranias, E.G., Mouse phospholamban gene expression during development in vivo and in vitro (1992) Circ Res, 71, pp. 1021-1030Ginsburg, K.S., Weber, C.R., Bers, D.M., Control of maximum sarcoplasmic reticulum Ca load in intact ferret ventricular myocytes. Effects of thapsigargin and isoproterenol (1998) J Gen Physiol, 111, pp. 494-504Hasenfuss, G., Alterations of calcium-regulatory proteins in heart failure (1998) Cardiovasc Res, 37, pp. 279-289Ito, K., Yan, X., Tajima, M., Su, Z., Barry, W.H., Lorell, B.H., Contractile reserve and intracellular calcium regulation in mouse myocytes from normal and hypertrophied failing hearts (2000) Circ Res, 87, pp. 588-595Janczewski, A.M., Zahid, M., Lemster, B.H., Frye, C.S., Gibson, G., Higuchi, Y., Kranias, E.G., McTiernan, C.F., Phospholamban gene ablation improves calcium transients but not cardiac function in a heart failure model (2004) Cardiovasc Res, 62, pp. 468-480Kim, D.H., Mkaparu, F., Kim, C., Caroll, R.F., Alterations of Ca 2+ release channel function in sarcoplasmic reticulum of pressure-overloadinduced hypertrophic rat heart (1994) J Mol Cell Cardiol, 26, pp. 1505-1512Linck, B., Bokník, P., Eschenhagen, T., Müller, F.U., Neumann, J., Nose, M., Jones, L.R., Scholz, H., Messenger RNA expression and immunological quantification of phospholamban and SR-Ca 2+-ATPase in failing and nonfailing human heart (1996) Cardiovasc Res, 31, pp. 625-632Maier, L.S., Bers, D.M., Calcium, calmodulin and calcium-calmodulin kinase II: Heartbeart to heartbeat and beyond (2002) J Mol Cell Cardiol, 34, pp. 919-939Maier, L.S., Brandes, R., Pieske, B., Bers, D.M., Effects of left ventricular hypertrophy on force and Ca 2+ handling in isolated rat myocardium (1998) Am J Physiol Heart Circ Physiol, 274, pp. H1361-H1370McCall, E., Ginsburg, S., Bassani, R.A., Shannon, T.R., Qi, M., Samarel, A.M., Bers, D.M., Ca flux, contractility, and excitation-contraction coupling in hypertrophic rat ventricular myocytes (1998) Am J Physiol Heart Circ Physiol, 274, pp. H1348-H1360Mészaros, J., Khananshvili, D., Hart, G., Mechanisms underlying delayed afterdepolarizations in hypertrophied left ventricle myocytes of rats (2001) Am J Physiol Heart Circ Physiol, 281, pp. H903-H914Minamisawa, S., Hoshijima, M., Chu, G., Ward, C.A., Frank, K., Gu, Y., Martone, M.E., Chien, K.R., Chronic phospholamban-sarcoplasmic reticulum interaction is the critical calcium cycling defect in dilated cardiomyopathy (1999) Cell, 99, pp. 313-322Miyamoto, M., Del Monte, F., Schmidt, U., Disalvo, T., Kang, Z.B., Matsui, T., Guerrero, J.L., Hajjar, R.J., Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure (2000) Proc Natl Acad Sci USA, 97, pp. 793-798Nadruz Jr., W., Kobarg, C.B., Constancio, S.S., Corat, P.D.C., Franchini, K.G., Load-induced transcription activation of c-jun in rat myocardium. Regulation by myocyte enhancer factor 2 (2003) Circ Res, 92, pp. 243-251Nakamura, A., Rokosh, D.G., Paccanaro, M., Yee, R.R., Simpson, P.C., Grossman, W., Foster, E., LV systolic performance improves with development of hypertrophy after transverse aortic constriction in mice (2001) Am J Physiol Heart Circ Physiol, 281, pp. H1104-H1112Nediani, C., Formigli, L., Perna, A.M., Ibba-Manneschi, L., Zecchi-Orlandini, S., Fiorillo, C., Ponziani, V., Nassi, P., Early changes induced in the left ventricle by pressure overload: An experimental study on swine heart (2000) J Mol Cell Cardiol, 32, pp. 131-142Ohkusa, T., Hisamatsu, Y., Yano, M., Kobayashi, S., Tatsuno, H., Saiki, Y., Kohno, M., Matsuzaki, M., Altered cardiac mechanism and sarcoplasmic reticulum function in pressure overload-induced cardiac hypertrophy in rats (1997) J Mol Cell Cardiol, 29, pp. 45-54Piacentino III, V., Weber, C.R., Chen, X., Weisser-Thomas, J., Margulies, K.B., Bers, D.M., Houser, S.R., Cellular basis of abnormal calcium transients of failing human ventricular myocytes (2003) Circ Res, 92, pp. 651-658Pogwizd, S.M., Schlotthauer, K., Li, L., Yuan, W., Bers, D.M., Arrhythmogenesis and contractile dysfunction in heart failure. Roles of sodiumcalcium exchange, inward rectifier potassium channels and residual β-adrenergic responsiveness (2001) Circ Res, 88, pp. 1159-1167Puglisi, J.L., Bassani, R.A., Bassani, J.W.M., Amin, J.N., Bers, D.M., Temperature and relative contributions of Ca transport systems in cardiac myocyte relaxation (1996) Am J Physiol Heart Circ Physiol, 270, pp. H1772-H1778Qi, M., Shannon, T.R., Euler, D.E., Bers, D.M., Samarel, A.M., Down-regulation of sarcoplasmic reticulum Ca 2+-ATPase during progression of left ventricular hypertrophy (1997) Am J Physiol Heart Circ Physiol, 272, pp. H2416-H2424Reinecke, H., Vetter, R., Drexler, H., Effects of α-adrenergic stimulation on the sarcolemmal Na +-Ca 2+-exchanger in adult rat ventricular cardiomyocytes (1997) Cardiovasc Res, 36, pp. 16-22Rodriguez, M.M., Chen, C.H., Smith, B.L., Mochly-Rosen, D., Characterization of the binding and phosphorylation of cardiac calsequestrin by ε protein kinase C (1999) FEBS Lett, 454, pp. 240-246Schultz, J.E.J., Glascock, B.J., Witt, S.A., Nieman, M.L., Nattamai, K.J., Liu, L.H., Lorenz, J.N., Periasamy, M., Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity (2004) Am J Physiol Heart Circ Physiol, 286, pp. H1146-H1153Scopacasa, B.S., Teixeira, V.P.A., Franchini, K.G., Colchicine attenuates left ventricular hypertrophy but preserves cardiac function of aorticconstricted rats (2003) J Appl Physiol, 94, pp. 1627-1633Shannon, T.R., Ginsburg, K.S., Bers, D.M., Potentiation of fractional SR Ca release by total and free intra-SR Ca concentration (2000) Biophys J, 78, pp. 334-343Shannon, T.R., Ginsburg, K.S., Bers, D.M., Quantitative assessment of the SR Ca 2+ leak-load relationship (2002) Circ Res, 91, pp. 594-600Shorofsky, S.R., Aggarwal, R., Corretti, M., Baffa, J.M., Strum, J.M., Al-Seikhan, B.A., Kobayashi, Y.M., Balke, C.W., Cellular mechanisms of altered contractility in the hypertrophied heart. Big hearts, big sparks (1999) Circ Res, 84, pp. 424-434Sipido, K.R., Volders, P.G.A., Groot, S.H.M., Verdonck, F., Werf, F., Wellens, H.J., Vos, M.A., Enhanced Ca 2+ release and Na/Ca exchange activity in hypertrophied canine ventricular myocytes. Potential link between contractile adaptation and arrhythmogenesis (2000) Circulation, 102, pp. 2137-2144Siri, F.M., Sympathetic changes during development of cardiac hypertrophy in aortic-constricted rats (1988) Am J Physiol Heart Circ Physiol, 255, pp. H425-H427Szymanska, G., Strömer, H., Kim, D.H., Lorell, B.H., Morgan, J.P., Dynamic changes in sarcoplasmic reticulum function in cardiac hypertrophy and failure (2000) Pflügers Arch, 439, pp. 339-348Tagawa, H., Wang, N., Narishige, T., Ingber, D.E., Zile, M.R., Cooper, I.V.G., Cytoskeletal mechanics in pressure-overload cardiac hypertrophy (1997) Circ Res, 80, pp. 281-289Torsoni, A.S., Fonseca, P.M., Crosara-Alberto, D.P., Franchini, K.G., Early activation of p160 ROCK by pressure overload in rat heart (2003) Am J Physiol Cell Physiol, 284, pp. C1411-C1419Trafford, A.W., Díaz, M.E., O'Neill, S.C., Eisner, D.A., Integrative analysis of calcium signaling in cardiac muscle (2002) Front Biosci, 1, pp. D843-D852Wehrens, X.H.T., Lehnart, S.E., Marks, A.R., Intracellular calcium release and cardiac disease (2005) Annu Rev Physiol, 67, pp. 69-98Zhang, T., Miyamoto, S., Brown, J.H., Cardiomyocyte calcium and calcium/calmodulin-dependent protein kinase II: Friends or foes? (2004) Recent Prog Horm Res, 59, pp. 141-16