Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure

Kushnir, Alexander; Santulli, Gaetano; Reiken, Steven; Coromilas, Ellie J.; Godfrey, Sarah; Brunjes, Danielle L.; Colombo, P.C.; Yuzefpolskaya, M.; Sokol, Seth I.; Kitsis, Richard N.; Marks, Andrew R.

doi:10.1161/circulationaha.117.032703

Cited by 41 publications

(33 citation statements)

References 64 publications

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“…Moreover, FGF21 deficiency exacerbated the development of diabetic cardiomyopathy by aggravating cardiac lipid accumulation [ 40 ]. In addition, it reported that inflammation plays a critical role of total cardiovascular disease, ischemic heart disease, and myocardial infarction [ 41 , 42 ]. Higher levels of circulating interleukin (IL)-8 were associated with larger infarct size and more adverse clinical outcomes in patients with ST-segment elevation myocardial infarction [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating level of fibroblast growth factor 21 is independently associated with the risks of unstable angina pectoris

Cheng

Qiao

et al. 2018

Bioscience Reports

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There is increasing evidence that serum adipokine levels are associated with higher risks of cardiovascular diseases. As an important adipokine, fibroblast growth factor 21 (FGF21) has been demonstrated to be associated with atherosclerosis and coronary artery disease (CAD). However, circulating level of FGF21 in patients with angina pectoris has not yet been investigated. Circulating FGF21 level was examined in 197 patients with stable angina pectoris (SAP, n=66), unstable angina pectoris (UAP, n=76), and control subjects (n=55) along with clinical variables of cardiovascular risk factors. Serum FGF21 concentrations on admission were significantly increased more in patients with UAP than those with SAP (Ln-FGF21: 5.26 ± 0.87 compared with 4.85 ± 0.77, P<0.05) and control subjects (natural logarithm (Ln)-FGF21: 5.26 ± 0.87 compared with 4.54 ± 0.72, P<0.01). The correlation analysis revealed that serum FGF21 concentration was positively correlated with the levels of cardiac troponin I (cTnI) (r2 = 0.026, P=0.027) and creatine kinase-MB (CK-MB) (r2 = 0.023, P= 0.04). Furthermore, FGF21 level was identified as an independent factor associated with the risks of UAP (odds ratio (OR): 2.781; 95% CI: 1.476–5.239; P=0.002), after adjusting for gender, age, and body mass index (BMI). However, there were no correlations between serum FGF21 levels and the presence of SAP (OR: 1.248; 95% CI: 0.703–2.215; P=0.448). The present study indicates that FGF21 has a strong correlation and precise predictability for increased risks of UAP, that is independent of traditional risk factors of angina pectoris.

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Section: Discussionmentioning

confidence: 99%

Circulating level of fibroblast growth factor 21 is independently associated with the risks of unstable angina pectoris

Cheng

Qiao

et al. 2018

Bioscience Reports

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“…To estimate myocardial infarct size, serum concentrations of troponin I were measured 1 d after coronary artery ligation via enzyme-linked immunosorbent assay (ELISA, Lifespan Biosciences, Seattle, WA, USA). Transthoracic ultrasound analysis was performed in anesthetized mice (isoflurane: 5% induction, 1.5% maintenance), as previously described [34,63,64].…”

Section: Animal Studiesmentioning

confidence: 99%

Cardiosomal microRNAs Are Essential in Post-Infarction Myofibroblast Phenoconversion

Morelli

Shu

Sardu

et al. 2019

IJMS

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The inclusion of microRNAs (miRNAs) in extracellular microvesicles/exosomes (named cardiosomes when deriving from cardiomyocytes) allows their active transportation and ensures cell-cell communication. We hypothesize that cardiosomal miRNAs play a pivotal role in the activation of myofibroblasts following ischemic injury. Using a murine model of myocardial infarction (MI), we tested our hypothesis by measuring in isolated fibroblasts and cardiosomes the expression levels of a set of miRNAs, which are upregulated in cardiomyocytes post-MI and involved in myofibroblast phenoconversion. We found that miR-195 was significantly upregulated in cardiosomes and in fibroblasts isolated after MI compared with SHAM conditions. Moreover, primary isolated cardiac fibroblasts were activated both when incubated with cardiosomes isolated from ischemic cardiomyocytes and when cultured in conditioned medium of post-MI cardiomyocytes, whereas no significant effect was observed following incubation with cardiosomes or medium from sham cardiomyocytes. Taken together, our findings indicate for the first time that a cardiomyocyte-specific miRNA, transferred to fibroblasts in form of exosomal cargo, is crucial in the activation of myofibroblasts.

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“…ER stress–induced abnormality of the intracellular Ca 2+ stores and the SR Ca 2+ release in the heart play prominent negative roles in cardiac contractile activation and relaxation (Eisner et al, 2000; Bers, 2002). Alterations in the sensitivity of ryanodine receptor (RyR) to Ca 2+ release activation have been involved in various diseases such as malignant hyperthermia and HF (Loke and MacLennan, 1998; Marx et al, 2000; Kushnir et al, 2018). Diastolic SR Ca 2+ leak decreased SR Ca 2+ load and reduced contractility along with cardiac output (Shan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Panax Notoginseng Saponins Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis

Xue

et al. 2019

Front. Pharmacol.

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Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Although Panax notoginseng saponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stress and its associated cell apoptosis along with the related mechanism in cardiac myocytes. PNS compounds were identified via high-performance liquid chromatograph (HPLC) assay. PNS-pretreated H9c2 cells, HL-1 cells, and primary cultured neonatal rat cardiomyocytes were stimulated with thapsigargin (TG) to induce ER stress response and apoptosis. ER stress response was tested by immunofluorescence or immunoblot of the ER protein chaperones—calnexin, binding immunoglobulin protein (BiP) and the C/EBP homologous protein (CHOP). Cell viability was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was detected by immunoblot of Cleaved caspase-3 and flow cytometry analysis of Annexin V/propidium iodide (PI) staining. Cytosolic, mitochondrial, and ER calcium dynamics were investigated by calcium imaging. Moreover, a ryanodine receptor type-2 (RyR2) overexpression stable cell line was generated to verify the mechanism of RyR2 involved in PNS in the inhibition of ER stress and cell apoptosis. We demonstrate here that PNS protected cardiac myocytes from ER stress response and associated cell death in a concentration-dependent manner. Importantly, PNS reduced the elevation of cytosolic calcium, mitochondria calcium, as well as ER calcium in response to either TG or histamine treatment. PNS protection in ER stress was regulated by RyR2 expression. In summary, PNS protection against TG-induced ER stress response and its associated cell apoptosis in cardiac myocytes is calcium dependent. Through the regulation of ER calcium release mediated by RyR2, a novel mechanism for PNS in the prevention of cardiovascular diseases is thereby identified.

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Ryanodine Receptor Calcium Leak in Circulating B-Lymphocytes as a Biomarker in Heart Failure

Cited by 41 publications

References 64 publications

Circulating level of fibroblast growth factor 21 is independently associated with the risks of unstable angina pectoris

Circulating level of fibroblast growth factor 21 is independently associated with the risks of unstable angina pectoris

Cardiosomal microRNAs Are Essential in Post-Infarction Myofibroblast Phenoconversion

Panax Notoginseng Saponins Protect Cardiac Myocytes Against Endoplasmic Reticulum Stress and Associated Apoptosis Through Mediation of Intracellular Calcium Homeostasis

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