Alterations in sarcoplasmic reticulum calcium-storing proteins in pressure-overload cardiac hypertrophy

Abstract

The alterations of intracellular calcium (Ca2+) homeostasis may be responsible for the contractile defects in pressure-overload cardiac hypertrophy. The Ca(2+)-adenosinetriphosphatase (ATPase) protein level of the sarcoplasmic reticulum (SR) is reduced in the hypertrophied or failing heart. However, it is not known whether Ca(2+)-storing proteins, including calsequestrin and calreticulin, are also altered during cardiac hypertrophy. We quantified SR Ca(2+)-regulatory proteins using Western blot analysis in left ventricular (LV) muscle isolated from sham-operated control rats (n = 6) and rats with pressure overload 4 wk after abdominal aortic constriction (n = 7). The contractile function of isolated LV myocytes, assessed by the sarcomere motion measured with laser diffraction, was depressed in aortic-constricted rats. The SR Ca(2+)-ATPase protein level was decreased to 56 +/- 9% (SE) of the control value in hypertrophied myocardium (P < 0.01). The calsequestrin protein level was not altered, whereas calreticulin was increased by 120 +/- 3% of the control value in aortic-constricted rats (P < 0.05). The alterations in SR Ca(2+)-regulatory proteins were equally observed in hypertrophied hearts even when the results were normalized using the amounts of myosin heavy chain proteins in each sample. Immunohistochemical staining of calsequestrin in the control heart showed cross striations at the Z lines, whereas calreticulin was hardly observed within myocytes but was intense within interstitial fibroblasts. In the hypertrophied heart, calreticulin was observed at the perinuclear region within the myocyte cytoplasm. These data indicate that pressure-overload cardiac hypertrophy causes the alterations in SR Ca(2+)-storing proteins as well as in Ca(2+)-ATPase, which may contribute to the contractile dysfunction of the hypertrophied myocytes.

Rescue of Contractile Parameters and Myocyte Hypertrophy in Calsequestrin Overexpressing Myocardium by Phospholamban Ablation

“…The increases in the expression levels of: (a) calreticulin, which has also been reported to increase in pressure overload hypertrophy (42) In the calsequestrin overexpressing heart as well as a variety of other experimental models, cardiac hypertrophy was associated with increased expression of fetal genes (23,(43)(44)(45). Interestingly, the up-regulation of ␣-skeletal actin and ANF mRNA was reversed by phospholamban ablation.…”

Cellular Distribution of Ca 2+ Pumps and Ca 2+ Release Channels in Rat Cardiac Hypertrophy Induced by Aortic Stenosis

“…SERCA 2 overexpression results in (1) increase in rate of the Ca 2ϩ transient decline and of cardiocyte relaxation indicating faster decrease in cytosolic Ca 2ϩ concentration, (2) increase in rate of myocyte shortening and of development of left ventricular pressure indicating faster Ca 2ϩ release, and (3) shortening of the time to half maximum postrest potentiation, indicating faster rate of SR Ca 2ϩ loading. In pressure overload-induced hypertrophy, prolonged myocardial relaxation has been demonstrated at the level of muscle fibers 18,42 or isolated myocytes 17 and was associated with reduced SERCA expression. On the other hand, SR function has been measured on total hearts and isolated cells in a similar model of hypertrophy.…”

Uremic Cardiomyopathy and Insulin Resistance

“…125 Recovery of the calcium transient is dependent on the sarcoplasmic calcium-ATPase (SERCA2a) and the sarcolemma sodium-calcium exchanger. In clinical and experimental studies, the transition from compensated hypertrophy to heart failure was associated with downregulation of SERCA2a expression, 126,127 which was also seen in experimental uremia. 123 Consequently, the uremic cardiomyocyte is desensitized to calcium, requiring greater diastolic and systolic intracellular calcium concentrations to maintain contraction.…”