Abnormalities of Calcium Cycling in the Hypertrophied and Failing Heart

Houser, Steven R.; Piacentino, Valentino; Weisser, Jutta

doi:10.1006/jmcc.2000.1206

Cited by 300 publications

(252 citation statements)

References 75 publications

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“…Whereas the observed reduction and prolongation of SR Ca release are hallmarks of failing myocardium (2,(14)(15)(16), the effects of HF on other EC parameters, including I Ca and SR Ca load, vary widely between different species and models. Our finding that alterations of SR Ca release occurred in the absence of significant changes in I Ca density but in parallel with a decrease in SR Ca content is consistent with results obtained previously in shorter term (3-6 weeks) canine models of tachypacing-induced HF (22,31).…”

Section: Defective Ryr Luminal Ca Regulation As a Cause Of Abnormal Camentioning

confidence: 99%

“…Evidence suggests that the amount of Ca released from the SR into the cytosol is reduced, accounting for, or contributing to, the reduced contractile force generated by the failing heart. In a majority of studies, including those in human cardiomyocytes, reduced SR Ca release has been shown to be associated with a decrease in the SR Ca content (2,(13)(14)(15)(16)(17). Several explanations have been put forth for the diminished SR Ca stores in HF.…”

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confidence: 99%

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Abnormal intrastore calcium signaling in chronic heart failure

Kubalova¹,

Terentyev²,

Viatchenko‐Karpinski³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

183

160

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Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intralu- excitation-contraction coupling ͉ ryanodine receptor ͉ sarcoplasmic reticulum

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Section: Defective Ryr Luminal Ca Regulation As a Cause Of Abnormal Camentioning

confidence: 99%

mentioning

confidence: 99%

Abnormal intrastore calcium signaling in chronic heart failure

Kubalova¹,

Terentyev²,

Viatchenko‐Karpinski³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

183

160

View full text Add to dashboard Cite

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“…In response to these effectors, the heart undergoes an adaptive response of compensatory hypertrophy (2) followed by decompensated heart failure that is characterized by defects in Ca 2ϩ handling during excitation-contraction coupling. Studies of end-stage-failing hearts have shown that the disturbed calcium homeostasis is associated with alterations in the expression levels or the activity of key Ca 2ϩ -handling proteins, leading to abnormal excitation contraction coupling and diastolic as well as systolic dysfunction (3,4). Specifically, alterations in SR 1 Ca 2ϩ -ATPase (SERCA2a) activity, the major Ca 2ϩ transport protein in SR, have been implicated as important determinants in the deteriorated function of the failing heart (5-7).…”

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confidence: 99%

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Haghighi

Schmidt

Hoit

et al. 2001

Journal of Biological Chemistry

115

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To determine whether selective impairment of cardiac sarcoplasmic reticulum (SR) Ca 2؉ transport may drive the progressive functional deterioration leading to heart failure, transgenic mice, overexpressing a phospholamban Val 49 3 Gly mutant (2-fold), which is a superinhibitor of SR Ca 2؉ -ATPase affinity for Ca 2؉, were generated, and their cardiac phenotype was examined longitudinally. At 3 months of age, the increased EC 50 level of SR Ca 2؉ uptake for Ca 2؉ (0.67 ؎ 0.09 M) resulted in significantly higher depression of cardiomyocyte rates of shortening (57%), relengthening (31%), and prolongation of the Ca 2؉ signal decay time (165%) than overexpression (2-fold) of wild type phospholamban (68%, 64%, and 125%, respectively), compared with controls (100%). Echocardiography also revealed significantly depressed function and impaired ␤-adrenergic responses in mutant hearts. The depressed contractile parameters were associated with left ventricular remodeling, recapitulation of fetal gene expression, and hypertrophy, which progressed to dilated cardiomyopathy with interstitial tissue fibrosis and death by 6 months in males. Females also had ventricular hypertrophy at 3 months but exhibited normal systolic function up to 12 months of age. These results suggest a causal relationship between defective SR Ca 2؉ cycling and cardiac remodeling leading to heart failure, with a gender-dependent influence on the time course of these alterations.Cardiac hypertrophy and failure are highly complex disorders that arise as a result of a combination of mechanical, hemodynamic, hormonal, and pathological stimuli (1). In response to these effectors, the heart undergoes an adaptive response of compensatory hypertrophy (2) followed by decompensated heart failure that is characterized by defects in Ca 2ϩ handling during excitation-contraction coupling. Studies of end-stage-failing hearts have shown that the disturbed calcium homeostasis is associated with alterations in the expression levels or the activity of key Ca 2ϩ -handling proteins, leading to abnormal excitation contraction coupling and diastolic as well as systolic dysfunction (3, 4). Specifically, alterations in SR 1 Ca 2ϩ -ATPase (SERCA2a) activity, the major Ca 2ϩ transport protein in SR, have been implicated as important determinants in the deteriorated function of the failing heart (5-7). The activity of SERCA2a is regulated by phospholamban (PLB), a 52-amino acid, muscle-specific SR phosphoprotein (8 -10). Dephosphorylated PLB inhibits the Ca 2ϩ affinity of SERCA2a, whereas the phosphorylated form of PLB dissociates from SERCA2a leading to increases in Ca 2ϩ uptake rates and accelerated ventricular relaxation (11-13).The role of PLB in the regulation of basal contractility has been elucidated through the development of genetically engineered mouse models. Phospholamban ablation resulted in significant increases in cardiac contractile parameters, whereas overexpressing PLB was associated with depressed cardiac function (14, 15). Actually, an inverse relationship betwe...

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“…This decrease in sarcoplasmic reticulum (SR) Ca 2ϩ transport function was thought to contribute to abnormalities in Ca 2ϩ handling and contractile dysfunction in failing hearts (14). Adenoviral gene transfer of SERCA is currently being explored as a new therapeutic approach for the treatment of heart failure (7,(26)(27)(28)(29).…”

mentioning

confidence: 99%

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

Huke

Prasad

Nieman

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Altered dose response to ␤-agonists in SERCA1a-expressing hearts ex vivo and in vivo. Am J Physiol Heart Circ Physiol 283: H958-H965, 2002; 10.1152/ ajpheart.00078.2002. -In this study we evaluated the contractile characteristics of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA)1a-expressing hearts ex vivo and in vivo and in particular their response to ␤-adrenergic stimulation. Analysis of isolated, work-performing hearts revealed that transgenic (TG) hearts develop much higher maximal rates of contraction and relaxation than wild-type (WT) hearts. Addition of isoproterenol only moderately increased the maximal rate of relaxation (ϩ20%) but did not increase contractility or decrease relaxation time in TG hearts. Perfusion with varied buffer Ca 2ϩ concentrations indicated an altered dose response to Ca 2ϩ . In vivo TG hearts displayed fairly higher maximal rates of contraction (ϩ 25%) but unchanged relaxation parameters and a blunted but significant response to dobutamine. Our study also shows that the phospholamban (PLB) level was decreased (Ϫ40%) and its phosphorylation status modified in TG hearts. This study clearly demonstrates that increases in SERCA protein level alter the ␤-adrenergic response and affect the phosphorylation of PLB. Interestingly, the overall cardiac function in the live animal is only slightly enhanced, suggesting that (neuro)hormonal regulations may play an important role in controlling in vivo heart function. transgenic mice; contractility; sarco(endo)plasmic reticulum calcium adenosinetriphosphatase; phospholamban SEVERAL STUDIES HAVE SHOWN that sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) activity is decreased in animal models of cardiac hypertrophy and failure as well as in human heart failure (11). This decrease in sarcoplasmic reticulum (SR) Ca 2ϩ transport function was thought to contribute to abnormalities in Ca 2ϩ handling and contractile dysfunction in failing hearts (14). Adenoviral gene transfer of SERCA is currently being explored as a new therapeutic approach for the treatment of heart failure (7,(26)(27)(28)(29).Recent studies have shown that the fast-twitch skeletal muscle isoform SERCA1 has a higher Ca 2ϩ uptake activity than the cardiac isoform SERCA2a because of a higher Ca 2ϩ turnover rate when expressed in cardiac myocytes (34). To test whether SERCA1a can functionally substitute for SERCA2a and increase cardiac contractility, we have developed a transgenic (TG) mouse model expressing SERCA1a in the heart (16,19,23). In this model, SERCA1a expression resulted in a 2.5-fold increase in total SERCA pump protein level, but the expression of the endogenous SERCA2a isoform was reduced to ϳ50% in TG hearts. As a consequence 20% of the total number of SERCA pumps in TG hearts were type 2a whereas the majority of 80% were type 1a pumps. The contractility of isolated TG hearts was clearly increased despite the reduced expression of SERCA2a (23). SERCA1a pump expression was well tolerated without any signs of hypertrophy or other pathophysiological changes in the...

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Abnormalities of Calcium Cycling in the Hypertrophied and Failing Heart

Cited by 300 publications

References 75 publications

Abnormal intrastore calcium signaling in chronic heart failure

Abnormal intrastore calcium signaling in chronic heart failure

Superinhibition of Sarcoplasmic Reticulum Function by Phospholamban Induces Cardiac Contractile Failure

Altered dose response to β-agonists in SERCA1a-expressing hearts ex vivo and in vivo

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