Sarcoplasmic reticulum function in the “stunned” myocardium

Limbruno, Ugo; Zucchi, Riccardo; Ronca-Testoni, S; Galbani, Paola; Ronca, G.; Mariani, Mario

doi:10.1016/0022-2828(89)90804-3

Cited by 71 publications

(21 citation statements)

References 34 publications

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“…The role of the SR in contractile dysfunction of stunned myocardium has not yet been clarified. Several researchers have said that the stunned myocardium induces a decrease in the ability to transport calcium, 30 and a reduction in the associated Ca-ATPase activity of the SR. 31 According to our present data, a marked reduction in Ca-ATPase activity was induced by reperfusion following 10 min of ischemia without degradation of the major ATPase protein. Our research group and others have proved that the SR function decreased in postischemic reperfused myocardium, but the biochemical mechanism responsible for the variation of the SR function still remains to be clarified.…”

Section: Calcium-stimulated Atpase Of the Sarcoplasmic Reticulumsupporting

confidence: 67%

Generation of Free Radicals and the Damage Done to the Sarcoplasmic Reticulum During Reperfusion Injury Following Brief Ischemia in the Canine Heart

et al. 1999

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Free radical generation was studied by the electron spin resonance (ESR) technique using -phenyl N tert butyl nitrone (PBN) in a brief ischemia-reperfusion model of the canine heart, and correlated with biochemical changes of the sarcoplasmic reticulum (SR). ESR spectra (aH = 0.3-0.4 mT, aN = 1.43-1.58 mT) were observed as PBN spin adducts, which peaked at levels 5-fold above the control levels at 5 min after reperfusion. The simulated coupling constants of PBN spin adducts suggested that the sample should contain at least 2 carbon-centered radicals at 5 min after reperfusion (radical A: aH = 0.350 mT, aN = 1.485 mT; radical B: aH = 0.370 mT, aN = 1.615 mT). At this time point, a significant reduction in Ca-ATPase activity of the SR was found without degradation of the major ATPase protein. Superoxide dismutase (SOD) significantly reduced the intensity of the PBN spin adduct signals and preserved the Ca-ATPase activity of the SR to 80% of the control level. Reperfusion injury after brief ischemia may be the result of inactivation of intracellular Ca-ATPase by free radicals generated during reperfusion, and SOD contributes to the protective effect by scavenging the radicals. (Jpn Circ J 1999; 63: 373 -378)

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Section: Calcium-stimulated Atpase Of the Sarcoplasmic Reticulumsupporting

confidence: 67%

Generation of Free Radicals and the Damage Done to the Sarcoplasmic Reticulum During Reperfusion Injury Following Brief Ischemia in the Canine Heart

et al. 1999

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“…These findings indicate that, although both PLB phosphorylation sites are involved in the mechanical recovery after ischemia, Thr 17 appears to play a major role. -ATPase 2 (SERCA2)] and/or in the rate of Ca 2ϩ reuptake by the SR have been described in several species, including rats, mice, dogs and humans, submitted to moderate and reversible injury during cardiac surgery (21,23,41,43). A decrease in the intracellular Ca 2ϩ transient has indeed been described in stunned myocytes isolated from chronically instrumented pigs (18) but was not detected in stunned rat myocytes and ventricular trabeculae or in isolated perfused ferret and dog hearts (5,9,11,18 appears to be normalized before complete recovery of myocardial performance in several species (5, 9, 11) does not necessarily mean that Ca 2ϩ homeostasis is not altered during ischemia and reperfusion.…”

mentioning

confidence: 99%

Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants

Said¹,

Vittone²,

Mundiña‐Weilenmann³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Said, M., L. Vittone, C. Mundiñ a-Weilenmann, P. Ferrero, E. G. Kranias, and A. Mattiazzi. Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants. uptake and myocardial contractility and relaxation. In perfused rat hearts submitted to ischemia-reperfusion, we previously showed an ischemia-induced Ser 16 phosphorylation that was dependent on ␤-adrenergic stimulation and an ischemia and reperfusion-induced Thr 17 phosphorylation that was dependent on Ca 2ϩ influx. To elucidate the relationship between these two PLB phosphorylation sites and postischemic mechanical recovery, rat hearts were submitted to ischemiareperfusion in the absence and presence of the CaMKII inhibitor KN-93 (1 M) or the ␤-adrenergic blocker dl-propranolol (1 M). KN-93 diminished the reperfusion-induced Thr 17 phosphorylation and depressed the recovery of contraction and relaxation after ischemia. dl-Propranolol decreased the ischemia-induced Ser 16 phosphorylation but failed to modify the contractile recovery. To obtain further insights into the functional role of the two PLB phosphorylation sites in postischemic mechanical recovery, transgenic mice expressing wild-type PLB (PLB-WT) or PLB mutants in which either Thr 17 or Ser 16 were replaced by Ala (PLB-T17A and PLB-S16A, respectively) into the PLB-null background were used. Both PLB mutants showed a lower contractile recovery than PLB-WT. However, this recovery was significantly impaired all along reperfusion in PLB-T17A, whereas it was depressed only at the beginning of reperfusion in PLB-S16A. Moreover, the recovery of relaxation was delayed in PLB-T17A, whereas it did not change in PLB-S16A, compared with PLB-WT. These findings indicate that, although both PLB phosphorylation sites are involved in the mechanical recovery after ischemia, Thr 17 appears to play a major role. -ATPase 2 (SERCA2)] and/or in the rate of Ca 2ϩ reuptake by the SR have been described in several species, including rats, mice, dogs and humans, submitted to moderate and reversible injury during cardiac surgery (21,23,41,43). A decrease in the intracellular Ca 2ϩ transient has indeed been described in stunned myocytes isolated from chronically instrumented pigs (18) but was not detected in stunned rat myocytes and ventricular trabeculae or in isolated perfused ferret and dog hearts (5,9,11,18 appears to be normalized before complete recovery of myocardial performance in several species (5, 9, 11) does not necessarily mean that Ca 2ϩ homeostasis is not altered during ischemia and reperfusion. There is a compelling body of evidence that indicates that in all species studied, cytosolic Ca 2ϩ concentration rises during ischemia (2,27,31). Furthermore, reperfusion in-

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“…The virtual suppression of Ca 2+ supply to the heart (70 µM (Ca) o + 0.4 µM nifedipine) significantly decreased 32 P incorporation into PLN ( 32 P-PLN), at 10, 30 and 300 nM Iso, but failed to affect it at 0.3 and 3 nM Iso. Data are reported as percent maximal 32 ( Figure 3B). However, when isoproterenol was perfused in the presence of low (Ca 2+ ) o , Ser 16 was the only site to show a concentration-dependent increase in phosphorylation ( Figure 3C).…”

Section: Role Of the Phosphorylation Of Thr 17 Of Pln During ß-Adrenementioning

confidence: 99%

“…On the other hand, experimental evidence indicates that the function of the SR is altered both in reversible and irreversible ischemiareperfusion injury (30)(31)(32)(33)(34). In particular, in the case of myocardial stunning, a decrease in the activity of SERCA2a and/or in the rate of Ca 2+ reuptake by the SR has been described in several species (31)(32)(33)(34).…”

Section: Stunningmentioning

confidence: 99%

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The importance of the Thr17 residue of phospholamban as a phosphorylation site under physiological and pathological conditions

Mattiazzi

Mundiña‐Weilenmann

Vittone

et al. 2006

Braz J Med Biol Res

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The sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA2a) is under the control of an SR protein named phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a, whereas phosphorylation of PLN at either the Ser 16 site by PKA or the Thr 17 site by CaMKII reverses this inhibition, thus increasing SERCA2a activity and the rate of Ca 2+ uptake by the SR. This leads to an increase in the velocity of relaxation, SR Ca 2+ load and myocardial contractility. In the intact heart, ß-adrenoceptor stimulation results in phosphorylation of PLN at both Ser 16 and Thr 17 residues. Phosphorylation of the Thr 17 residue requires both stimulation of the CaMKII signaling pathways and inhibition of PP1, the major phosphatase that dephosphorylates PLN. These two prerequisites appear to be fulfilled by ß-adrenoceptor stimulation, which as a result of PKA activation, triggers the activation of CaMKII by increasing intracellular Ca 2+ , and inhibits PP1. Several pathological situations such as ischemia-reperfusion injury or hypercapnic acidosis provide the required conditions for the phosphorylation of the Thr 17 residue of PLN, independently of the increase in PKA activity, i.e., increased intracellular Ca 2+ and acidosis-induced phosphatase inhibition. Our results indicated that PLN was phosphorylated at Thr 17 at the onset of reflow and immediately after hypercapnia was established, and that this phosphorylation contributes to the mechanical recovery after both the ischemic and acidic insults. Studies on transgenic mice with Thr 17 mutated to Ala (PLN-T17A) are consistent with these results. Thus, phosphorylation of the Thr 17 residue of PLN probably participates in a protective mechanism that favors Ca 2+ handling and limits intracellular Ca 2+ overload in pathological situations.

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Sarcoplasmic reticulum function in the “stunned” myocardium

Cited by 71 publications

References 34 publications

Generation of Free Radicals and the Damage Done to the Sarcoplasmic Reticulum During Reperfusion Injury Following Brief Ischemia in the Canine Heart

Generation of Free Radicals and the Damage Done to the Sarcoplasmic Reticulum During Reperfusion Injury Following Brief Ischemia in the Canine Heart

Role of dual-site phospholamban phosphorylation in the stunned heart: insights from phospholamban site-specific mutants

The importance of the Thr17 residue of phospholamban as a phosphorylation site under physiological and pathological conditions

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