Human electronegative low-density lipoprotein modulates cardiac repolarization via LOX-1-mediated alteration of sarcolemmal ion channels

Lee, An‐Sheng; Xi, Yutao; Lai, Chin-Hu; Chen, Wei-Yu; Peng, Hsien Yu; Chan, Hua‐Chen; Chen, Chu‐Huang; Chang, Kuan‐Cheng

doi:10.1038/s41598-017-10503-x

Cited by 5 publications

(8 citation statements)

References 55 publications

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“…In CMs, L5 has recently been shown to induce abnormal electrophysiologic activities, such as prolonged action potential duration (APD) [11]. In this study, L5 significantly prolonged the APD in NRCMs (Fig.…”

Section: L5 Prolongs Action Potential Duration (Apd) In Nrcmsmentioning

confidence: 50%

“…In addition, L5 levels have been shown to correlate with the prolonged duration of QTc intervals in patients with CHD. This prolongation was modulated by the alteration of the I CaL (L-type calcium current) and I To (transient outward potassium current) [11]. Dysfunctional potassium channels primarily affect cardiac conduction, as evidenced by altered PR and QTc intervals, as well as APD alternans.…”

Section: Discussionmentioning

confidence: 99%

“…In cultured cardiomyocytes (CMs), L5 has been reported to induce cell apoptosis via cytokines released from vascular endothelial cells [10]. Recently, it has been demonstrated that L5 causes prolongation of the corrected QT interval (QTc) by mediating the current of L-type calcium and transient activated potassium channels [11]. Functional ATP-sensitive potassium channels (K ATP ) are essential for ischemic preconditioning, post-ischemia cardiac protection, and regulation of atrial and ventricular rhythm during cardiac ischemia [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

Cheng

Sun

et al. 2020

Lipids Health Dis

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Background: Cardiac Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (K ATP) channels are essential for cardiac protection during ischemia. In cultured CMs, L5 low-density lipoprotein (LDL) induces apoptosis and QTc prolongation. L5 is a highly electronegative and atherogenic aberrant form of LDL, and its levels are significantly higher in patients with cardiovascular-related diseases. Here, the role of L5 in cardiac injury was studied by evaluating the effects of L5 on CaMKII activity and K ATP channel physiology in CMs. Methods: Cultured neonatal rat CMs (NRCMs) were treated with a moderate concentration (ie, 7.5 μg/mL) of L5 or L1 (the least electronegative LDL subfraction). NRCMs were examined for apoptosis and viability, CaMKII activity, and the expression of phosphorylated CaMKIIδ and NOX2/gp91 phox. The function of K ATP and action potentials (APs) was analyzed by using the patch-clamp technique. Results: In NRCMs, L5 but not L1 significantly induced cell apoptosis and reduced cell viability. Furthermore, L5 decreased Kir6.2 expression by more than 50%. Patch-clamp analysis showed that L5 reduced the K ATP current (I KATP) density induced by pinacidil, a K ATP opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the I KATP blocker glibenclamide. Suppression of I KATP by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91 phox. L5-induced apoptosis was prevented by the addition of the CaMKII inhibitor KN93 and the reactive oxygen species scavenger Mn (III)TBAP. Conclusions: L5 but not L1 induces CM damage through the activation of the CaMKII pathway and increases arrhythmogenicity in CMs by modulating the AP duration. These results help to explain the harmful effects of L5 in cardiovascular-related disease.

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Section: L5 Prolongs Action Potential Duration (Apd) In Nrcmsmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

Cheng

Sun

et al. 2020

Lipids Health Dis

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“…The whole‐cell patch‐clamp technique was used to record membrane potential in current‐clamp mode and ionic currents in voltage‐clamp mode with the Axon CNS 700B amplifier (Molecular Devices), the Axon Digidata 1550 data acquisition system, and the pClamp software (Version 10.5, Molecular Devices) . Patch electrodes were prepared from borosilicate glass capillaries (TW150‐3, World Precision Instrument, Inc.,) with around 1.3 MΩ pipette resistance.…”

Section: Methodsmentioning

confidence: 99%

Cardiac protection of Bauhinia championii against reperfusion injury

Chen

Chung

et al. 2020

Environmental Toxicology

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This study aims to investigate the protective effects of the Bauhinia championii (BC) against ischemia/reperfusion (I/R)-induced injury in an isolated heart model.Langendorff-perfused C57BL/6JNarl mice hearts were performed with 30 minutes ischemia and 60 minutes reperfusion by left anterior descending artery ligation.Before reperfusion, boiling water extracts of BC (10 mg/L) was pretreated for 15 minutes. During reperfusion, BC significantly decreased the occurrence of ventricular arrhythmias by lead II electrocardiogram (ECG). Electrophysiological effect of BC was further determined in isolated ventricular myocytes by whole-cell patch clamp technique. The underlying mechanism may result from its Na + channel blocking activity characterized with reduced rise slope of action potential and Na + current density.Moreover, BC dramatically reduced I/R-caused infarct size, which was accessed by 2,3,5-triphenyltetrazolium chloride (TTC) assay. Since BC decreased I/R-induced myoglobin release and oxidation of Ca 2+ -calmodulin-dependent protein kinase, inhibition of myocardial necroptosis may account for the protective effects of BC on myocytes lose. This study indicated that BC may prevent I/R induced ventricular arrhythmias and myocyte death by blocking Na + channels and decreasing necroptosis, respectively. Since most of the available antiarrhythmic remedies have unwanted adverse actions, BC could be a novel candidate for the treatment of myocardial infarction and ventricular arrhythmia. K E Y W O R D S arrhythmias, Bauhinia championii, ischemia/reperfusion, sodium current

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“…Accumulating evidence suggests that L5 LDL interacts with multiple cells such as endothelial cells [ 8 , 15 , 56 , 57 , 58 ], platelets [ 10 , 11 ], monocytes [ 9 , 59 , 60 , 61 , 62 , 63 ], and cardiomyocytes [ 24 , 64 , 65 , 66 , 67 ]. L5 LDL attracts both monocytes and lymphocytes to endothelial cells (ECs) [ 58 ], indicating the contribution in the early stage of atherosclerosis.…”

Section: Cellular Signaling Of L5 Ldlmentioning

confidence: 99%

Clinical Significance of Electronegative Low-Density Lipoprotein Cholesterol in Atherothrombosis

et al. 2020

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Despite the numerous risk factors for atherosclerotic cardiovascular diseases (ASCVD), cumulative evidence shows that electronegative low-density lipoprotein (L5 LDL) cholesterol is a promising biomarker. Its toxicity may contribute to atherothrombotic events. Notably, plasma L5 LDL levels positively correlate with the increasing severity of cardiovascular diseases. In contrast, traditional markers such as LDL-cholesterol and triglyceride are the therapeutic goals in secondary prevention for ASCVD, but that is controversial in primary prevention for patients with low risk. In this review, we point out the clinical significance and pathophysiological mechanisms of L5 LDL, and the clinical applications of L5 LDL levels in ASCVD can be confidently addressed. Based on the previously defined cut-off value by receiver operating characteristic curve, the acceptable physiological range of L5 concentration is proposed to be below 1.7 mg/dL. When L5 LDL level surpass this threshold, clinically relevant ASCVD might be present, and further exams such as carotid intima-media thickness, pulse wave velocity, exercise stress test, or multidetector computed tomography are required. Notably, the ultimate goal of L5 LDL concentration is lower than 1.7 mg/dL. Instead, with L5 LDL greater than 1.7 mg/dL, lipid-lowering treatment may be required, including statin, ezetimibe or PCSK9 inhibitor, regardless of the low-density lipoprotein cholesterol (LDL-C) level. Since L5 LDL could be a promising biomarker, we propose that a high throughput, clinically feasible methodology is urgently required not only for conducting a prospective, large population study but for developing therapeutics strategies to decrease L5 LDL in the blood.

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Human electronegative low-density lipoprotein modulates cardiac repolarization via LOX-1-mediated alteration of sarcolemmal ion channels

Cited by 5 publications

References 55 publications

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation

Cardiac protection of Bauhinia championii against reperfusion injury

Clinical Significance of Electronegative Low-Density Lipoprotein Cholesterol in Atherothrombosis

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