Loss of CASK Accelerates Heart Failure Development

Mustroph, Julian; Sag, Can Martin; Bähr, Felix Lucas; Schmidtmann, Anna-Lena; Gupta, Sidhi; Dietz, A.; Islam, Md. Monirul; Lücht, Charlotte M.; Beuthner, Bo Eric; Pabel, Steffen; Baier, Maria J.; El‐Armouche, Ali; Sossalla, Samuel; Anderson, Mark E.; Möllmann, Julia; Lehrke, Michael; Mohler, Peter J.; Bers, Donald M.; Unsöld, Bernhard; He, Tao; Dewenter, Matthias; Backs, Johannes; Maier, Lars S.; Wagner, Stefan

doi:10.1161/circresaha.120.318170

Cited by 12 publications

(12 citation statements)

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“… 51 Along those lines, the related drug exenatide induced of CASK (Ca/CaM dependent serine protein kinase) that inhibit CaMKII and could partially ameliorate hyperglycemic effects that we described here. 52 Moreover, empagliflozin blunted postprandial glucose excursions and reduced glucose-variability in patients with diabetes, which may attenuate O -GlcNAc-dependent CaMKII activation. 53 In line with this, dapagliflozin, another SGLT2 inhibitor was shown to reduce O -GlcNAcylated protein levels in a type 2 diabetic murine model.…”

Section: Discussionmentioning

confidence: 99%

CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia

Hegyi

Fasoli

et al. 2021

Circulation Research

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Rationale: Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and calcium/calmodulin-dependent protein kinase II (CaMKII) function has been implicated. CaMKII activity is promoted by both oxidation and O linked β-N-acetylglucosamine (O GlcNAc) of known CaMKII sites. Objective: To investigate which post-translational modifications occur in human diabetic hearts and how they alter electrophysiological and Ca 2+ handling properties in hyperglycemia. Methods and Results: We assessed echocardiography, electrophysiology, Ca 2+ -handling, and protein expression in site-specific CaMKII mutant mice (O GlcNAc-resistant S280A and oxidation-resistant MM281/2VV knock-ins, and global and cardiac-specific knockouts), in myocytes subjected to acute hyperglycemia and angiotensin II (Ang-II) and mice after streptozotocin injections (to induce diabetes). Human patients with diabetes exhibit elevated CaMKII O GlcNAcylation but not oxidation. In mice, acute hyperglycemia increased spontaneous diastolic Ca 2+ sparks and waves and arrhythmogenic action potential changes (prolongation, alternans and delayed afterdepolarizations), all of which required CaMKII-S280 O GlcNAcylation. Ang-II effects were dependent on NADPH oxidase 2 (NOX2)-mediated CaMKII MM281/2 oxidation. Diabetes led to much greater Ca 2+ leak, RyR2 S2814 phosphorylation, electrophysiological remodeling, and increased susceptibility to in vivo arrhythmias, requiring CaMKII activation, predominantly via S280 O GlcNAcylation and less via MM281/2 oxidation. These effects were present in myocytes at normal glucose, but were exacerbated with the in-vivo high circulating glucose. Phospholamban (PLB) O-GlcNAcylation was increased and coincided with reduced PLB S16 phosphorylation in diabetes. Dantrolene, that reverses CaMKII-dependent proarrhythmic RyR-mediated Ca 2+ leak, also prevented hyperglycemia-induced APD prolongation and delayed afterdepolarizations. Conclusions: We found that CaMKII-S280 O GlcNAcylation is required for increased arrhythmia susceptibility in diabetic hyperglycemia, which can be worsened by an additional angiotensin II-NOX2-CaMKII MM281/2 oxidation pathway. CaMKII-dependent RyR2 S2814 phosphorylation markedly increases proarrhythmic Ca 2+ leak and PLB O-GlcNAcylation may limit SR Ca 2+ reuptake, leading to impaired excitation-contraction coupling and arrhythmogenesis in diabetic hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia

Hegyi

Fasoli

et al. 2021

Circulation Research

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“…Western blots were performed to confirm key results, as described elsewhere (21). Briefly, left ventricular myocardium was mechanically homogenized (using a stainless steel pestle) in Tris buffer containing (in mmol/L): 50 Tris-HCl, 200 NaCl, 20 NaF, 1 Na 3 VO 4 , 1 DTT [pH 7.4] and protease inhibitor cocktail.…”

Section: Western Blotsmentioning

confidence: 99%

Cardiac Fibrosis Is a Risk Factor for Severe COVID-19

et al. 2021

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Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor β1 (TGF-β1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-β1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-β1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-β1 mRNA performed at the time of first medical contact.

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“…Western Blot analysis was performed as described previously [ 6 ]. Briefly, LV myocardium was mechanically homogenized (using a stainless steel pestle) in Tris buffer containing (in mmol/L): 50 Tris–HCl, 200 NaCl, 20 NaF, 1 Na 3 VO 4 , 1 DTT [pH 7.4] and protease inhibitor cocktail.…”

mentioning

confidence: 99%