Cardiac SERCA2A/B: Therapeutic targets for heart failure

Shareef, Mohammad Abrar; Anwer, Lucman A.; Poizat, Coralie

doi:10.1016/j.ejphar.2013.12.018

Cited by 68 publications

(41 citation statements)

References 99 publications

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“…In contrast to the strong effect of LRP1 deficiency on SERCA2, LRP1 deficiency does not prevent the downregulatory effect of hypoxia on NCX-1 and CAV1.2. These results support a pivotal role of SERCA2 on the maintenance of calcium metabolism and are in agreement with the enormous potential of SERCA2 restoration by pharmacological action or gene delivery in the treatment of heart failure [37][38][39].…”

Section: Impact Of Lrp1 Deficiency On Calcium-handling Proteins and Csupporting

confidence: 87%

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Revuelta‐López¹,

Cal²,

Herraiz‐Martínez³

et al. 2015

Journal of Molecular and Cellular Cardiology

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Section: Impact Of Lrp1 Deficiency On Calcium-handling Proteins and Csupporting

confidence: 87%

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Revuelta‐López¹,

Cal²,

Herraiz‐Martínez³

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…By sequestering cytosolic calcium in the endoplasmic reticulum, SERCA further regulates important signaling mechanisms critical for normal cell function, growth, and survival. Under conditions of heart failure, decreased Ca 21 uptake due to loss of SERCA activity is observed in humans, as well as in animal models of heart failure (35). Irreversible oxidation of SERCA and subsequent loss of activity occurs in the presence of higher levels of reactive oxygen species (36).…”

Section: Discussionmentioning

confidence: 99%

Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

Ahmad

Hendry‐Hofer

et al. 2015

Am J Respir Cell Mol Biol

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Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation-induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute highconcentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration-approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia-reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine-and istaroximetreated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure. Clinical RelevanceThis study defines impact of inhalation of a toxic gas, chlorine, on a critical cardiac calcium pump, sarcoendoplasmic reticulum Ca 21 ATPase (SERCA). It also demonstrates that therapeutic strategies that protect or modify SERCA function could be useful approaches for emergent resuscitation of severe chlorine inhalation victims.Chlorine is a commonly used chemical in industry and society. Acute chlorine inhalation toxicity can occur due to accidents at swimming pools and/or involving water purification systems, after transportation accidents, upon industrial exposure, with misuse of domestic cleaners, during military operations, and, more recently, through chemical terrorism. In the

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“…Age, pulmonary artery wedge pressure, LVEDVI, study. 12,13 SERCA2α, in particular, has received considerable attention as a therapeutic target for heart failure, 24 because SERCA2α gene therapy appears to improve ventricular contractility and reduce the incidence of lethal arrhythmias in animal models. 25, 26 Furthermore, several clinical trials are investigating the potential benefit of SERCA2α gene therapy for systolic heart failure.…”

Section: Comparison Of the Cvf In The Bif And Mof Groupsmentioning

confidence: 99%

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy

Morimoto

Okumura

Bando

et al. 2017

Circ J

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Background:The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dtmax) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patient's prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM). Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern. Conclusions:The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.

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Cardiac SERCA2A/B: Therapeutic targets for heart failure

Cited by 68 publications

References 99 publications

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy

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Cardiac SERCA2A/B: Therapeutic targets for heart failure

Cited by 68 publications

References 99 publications

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Hypoxia-driven sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) downregulation depends on low-density lipoprotein receptor-related protein 1 (LRP1)-signalling in cardiomyocytes

Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy

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Sarcoendoplasmic Reticulum Ca²⁺ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity