Modulating sarco(endo)plasmic reticulum Ca2+ ATPase 2 (SERCA2) activity: Cell biological implications

Vangheluwe, Peter; Raeymaekers, Luc; Dode, Leonard; Wuytack, Frank

doi:10.1016/j.ceca.2005.06.033

Cited by 182 publications

(150 citation statements)

References 112 publications

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“…The density of the calcium release-triggering ryanodine receptor is decreased on the SR during experimental sepsis, associated with subsequent impairment of Ca 2+ release from the sarcoplasmic reticulum (67 (68). Dephosphorylated PLB activates and enhances SERCA2 activity, whereas phosphorylation of PLB greatly diminishes SERCA2 functionality and myocardial relaxation (68,69). Thus, PLB and SERCA2 interactions play a primary role in regulating cardiac contractility and relaxation.…”

Section: Calcium Flux and Cardiomyofilamentsmentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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Septic cardiomyopathy is a well-described complication of severe sepsis and septic shock. However, the interplay of its underlying mechanisms remains enigmatic. Consequently, we constantly add to our pathophysiological understanding of septic cardiomyopathy. Various cardiosuppressive mediators have been discovered, as have multiple molecular mechanisms (alterations of myocardial calcium homeostasis, mitochondrial dysfunction, and myocardial apoptosis) that may be involved in myocardial dysfunction during sepsis. Finally, the detrimental roles of nitric oxide and peroxynitrite have been unraveled. Here, we describe our present understanding of systemic, supracellular, and cellular molecular mechanisms involved in sepsis-induced myocardial suppression. SYSTEMIC, SUPRACELLULAR MECHANISMS Decreased Coronary Blood FlowOne of the first suggestions was that reduced coronary perfusion in the septic heart might be responsible for a setting of global cardiac ischemia. This hypothesis was soon abandoned after direct measurements of coronary blood flow were obtained, showing no reduced, but rather increased, coronary blood flow (22,23). In later studies, however, increased levels of plasma troponin were observed and correlated with the severity of myocardial depression during sepsis and septic shock (24). Myocardial necrosis could not be observed in patients who died from septic shock (3,25), however, raising the question whether increases in troponin were due to cytokine-induced, transient increases in cardiomyocyte membrane permeability to troponin. To date, this remains to be determined. Alterations of MicrovasculatureThere is now increasing evidence that sepsis and septic shock leads to changes of the myocardial microvasculature. In a canine model of endotoxemia, maldistribution of heterogeneous coronary blood flow has been reported (26). These findings might be caused by endothelial swelling and nonocclusive intravascular fibrin deposits in the microvasculature (27). In parallel, activated cardiomyocytes from septic mice promoted transendothelial migration and activation of circulating neutrophils into the interstitium (28) where these cells may augment the sepsis-induced intracardial inflammation, and contribute to an increased vascular leakage, which has been described to also impair cardiac function and compliance secondary to myocardial edema (29,30). Yet, studies have failed to confirm cellular hypoxia in a murine sepsis model (31). Cardiosuppressing Circulating Proinflammatory MediatorsAnother hypothesis suggested circulating myocardium-depressing factors as the cause of septic cardiomyopathy (32). Parrillo et al. (33) confirmed the existence of a cardiodepressant substance by incubating isolated rat cardiomyocytes with serum obtained from septic shock patients, leading to decreased amplitude and velocity of cardiomyocyte shortening. Levels of cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and the complement anaphylatoxin, C5a, are known to be elevated in the circulation during sepsis an...

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Section: Calcium Flux and Cardiomyofilamentsmentioning

confidence: 99%

Molecular Events in the Cardiomyopathy of Sepsis

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

109

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“…Suppressing SERCA activity by inhibitor thapsigargin depletes the EnR Ca 2+ pool, triggering EnR stress and cell death (6). Of the three SERCA family members (SERCA1, SERCA2, and SERCA3), SERCA1 and SERCA3 are expressed in muscle cells or nonmuscle cells in a tissue-specific manner, whereas SERCA2 is ubiquitously expressed (7). SERCA2 exists in two isoforms: SERCA2a is expressed in cardiac and slow-twitch muscles, whereas SERCA2b, with a C-terminal extension, is the housekeeping isoform expressed in smooth muscles and nonmuscle cells.…”

mentioning

confidence: 99%

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Wang

Zhou

Phung

et al. 2017

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

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Many estrogen receptor alpha (ERα)-positive breast cancers initially respond to aromatase inhibitors (AIs), but eventually acquire resistance. Here, we report that serum-and glucocorticoid-inducible kinase 3 (SGK3), a kinase transcriptionally regulated by ERα in breast cancer, sustains ERα signaling and drives acquired AI resistance. SGK3 is up-regulated and essential for endoplasmic reticulum (EnR) homeostasis through preserving sarcoplasmic/EnR calcium ATPase 2b (SERCA2b) function in AI-resistant cells. We have further found that EnR stress response down-regulates ERα expression through the protein kinase RNA-like EnR kinase (PERK) arm, and SGK3 retains ERα expression and signaling by preventing excessive EnR stress. Our study reveals regulation of ERα expression mediated by the EnR stress response and the feed-forward regulation between SGK3 and ERα in breast cancer. Given SGK3 inhibition reduces AI-resistant cell survival by eliciting excessive EnR stress and also depletes ERα expression/function, we propose SGK3 inhibition as a potential effective treatment of acquired AI-resistant breast cancer.SGK3 | aromatase inhibitor | endoplasmic reticulum stress | estrogen receptor | SERCA2

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“…28) SERCA, mainly represented by the SERCA2a isoform in the heart, determines the Ca 2+ loading of the sarco(endo)plasmic reticulum and therefore the amount of Ca 2+ released and cardiac contractility. 28,29) Thus, the activity of SERCA and the SERCA2a protein levels are also important determinants of cell function and metabolic activity. The results of the ATPase assays and Western blotting imply that CFderived ECM elevates ventricular cell function and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Cardiac Fibroblast-Derived Extracellular Matrix Produced <I>In Vitro</I> Stimulates Growth and Metabolism of Cultured Ventricular Cells

et al. 2013

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SummaryCardiac fi broblasts (CFs) produce extracellular matrix (ECM) which is a potent regulator of heart cell function and growth, and provides a supportive microenvironment for heart cells. Therefore, CF-derived ECM produced in vitro is very suitable for heart-cell culturing and cardiac tissue engineering. The aim of this study was to investigate the effect of CF-derived ECM produced in vitro on the growth and metabolism of cultured ventricular cells. CF-derived ECM-coated cell culture dishes were prepared by culturing rat CFs and then decellularizing the cultures. Isolated neonatal rat ventricular cells were seeded on ECM-coated, collagen I-coated or uncoated dishes, and the growth of cells after 1-5 days of culture was assayed with MTT reagent. In addition, cellular metabolic activity was analyzed by spectrophotometric methods and protein levels of sarco(endo)plasmic reticulum Ca 2+ -ATPase type 2a (SERCA2a) by Western blotting. The relative growth of ventricular cells was better on ECM-coated than on uncoated or collagen I-coated dishes. Furthermore, the glucose consumption ratio, lactic acid production ratio, Na + /K + -ATPase activity, SERCA activity and protein levels of SERCA2a were all higher in cells on the ECM-coated dishes. In conclusion, cardiac fi broblast-derived ECM produced in vitro stimulates the growth and metabolism of cultured ventricular cells. This study indicates that the bioactivity of the ECM supports heart cell growth in vitro, and this might be useful for cardiac tissue engineering. (Int Heart J 2013; 54: 40-44)

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Modulating sarco(endo)plasmic reticulum Ca2+ ATPase 2 (SERCA2) activity: Cell biological implications

Cited by 182 publications

References 112 publications

Molecular Events in the Cardiomyopathy of Sepsis

Molecular Events in the Cardiomyopathy of Sepsis

SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis

Cardiac Fibroblast-Derived Extracellular Matrix Produced <I>In Vitro</I> Stimulates Growth and Metabolism of Cultured Ventricular Cells

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