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Ziolo, Mark T.; Sondgeroth, Korie; Harshbarger, C H; Smith, Jacquelyn M.; Wahler, Gordon M.

doi:10.1023/a:1010992900387

Cited by 8 publications

(6 citation statements)

References 38 publications

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“…Currently, the data presented above are in opposition to earlier results of others. Previous reports have demonstrated that PC may strongly activate [ 3 , 4 ] and inhibit [ 4 , 5 ] L-type Ca 2+ current (Ica 2+ ). The experiments performed on LCC, incorporated in the lipid bilayer, revealed strong dose-dependent and time-dependent effects of PC on open probability of the channels, with maximal effect achieved at 1 µM PC and within the first minutes of the recording [ 4 ].…”

Section: Resultsmentioning

confidence: 99%

“…The experiments performed on LCC, incorporated in the lipid bilayer, revealed strong dose-dependent and time-dependent effects of PC on open probability of the channels, with maximal effect achieved at 1 µM PC and within the first minutes of the recording [ 4 ]. Although, according to the results of the experiments on isolated CM, 10 µM PC exerted immediate inhibition of Ica 2+ [ 5 ].…”

Section: Resultsmentioning

confidence: 99%

“…Besides, it was shown in [ 2 ] that palmitoylcarnitine (PC), known ischemic metabolite, induced Ca 2+ overload, implicating L-type calcium channels (LCC) and Ca 2+ release from the sarcoplasmic/endoplasmic reticulum (SR/ER) stores. At this time it was determined that long-chain fatty acids (LCFA) or respective acylcarnitines (LCAC) may activate or inhibit LCC [ 3 , 4 , 5 ] and activate SR/ER calcium channels [ 6 , 7 , 8 ]. A few years later, it was recognized that limited mitochondrial Ca 2+ buffering capacity and mitochondrial permeability transition pore (mPTP) induction may underlie the deterioration of cellular Ca 2+ homeostasis in CM in I/R [ 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines-Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-Dependent Phospholipases, and Mitochondrial Energetics Collapse

Berezhnov

Fedotova

Nenov

et al. 2020

IJMS

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Long-chain acylcarnitines (LCAC) are implicated in ischemia-reperfusion (I/R)-induced myocardial injury and mitochondrial dysfunction. Yet, molecular mechanisms underlying involvement of LCAC in cardiac injury are not sufficiently studied. It is known that in cardiomyocytes, palmitoylcarnitine (PC) can induce cytosolic Ca2+ accumulation, implicating L-type calcium channels, Na+/Ca2+ exchanger, and Ca2+-release from sarcoplasmic reticulum (SR). Alternatively, PC can evoke dissipation of mitochondrial potential (ΔΨm) and mitochondrial permeability transition pore (mPTP). Here, to dissect the complex nature of PC action on Ca2+ homeostasis and oxidative phosphorylation (OXPHOS) in cardiomyocytes and mitochondria, the methods of fluorescent microscopy, perforated path-clamp, and mitochondrial assays were used. We found that LCAC in dose-dependent manner can evoke Ca2+-sparks and oscillations, long-living Ca2+ enriched microdomains, and, finally, Ca2+ overload leading to hypercontracture and cardiomyocyte death. Collectively, PC-driven cardiotoxicity involves: (I) redistribution of Ca2+ from SR to mitochondria with minimal contribution of external calcium influx; (II) irreversible inhibition of Krebs cycle and OXPHOS underlying limited mitochondrial Ca2+ buffering; (III) induction of mPTP reinforced by PC-calcium interplay; (IV) activation of Ca2+-dependent phospholipases cPLA2 and PLC. Based on the inhibitory analysis we may suggest that simultaneous inhibition of both phospholipases could be an effective strategy for protection against PC-mediated toxicity in cardiomyocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines-Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-Dependent Phospholipases, and Mitochondrial Energetics Collapse

Berezhnov

Fedotova

Nenov

et al. 2020

IJMS

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“…Finally, fatty acids are a major source of energy for the heart 30 . A shift in substrate preference occurs in diseases that increase the risk of SCA, including cardiac hypertrophy 31 and uncontrolled diabetes 32 ; and accumulation of intermediates of fatty acid oxidation influence arrhythmogenesis in isolated cardiac tissues and cardiac myocytes 33, 34 . For these reasons, we examined genes that may be involved in the uptake and transport of fatty acids in the heart, fatty acid beta-oxidation in mitochondria and the control of beta-oxidation.…”

Section: Discussionmentioning

confidence: 99%

Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

et al. 2014

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Background There is limited information on genetic factors associated with sudden cardiac arrest (SCA). Objective To assess the association of common variation in genes in fatty acid pathways with SCA risk. Methods We selected 85 candidate genes and 1155 single nucleotide polymorphisms (SNPs) tagging common variation in each gene. We investigated the SNP associations with SCA in a population-based case-control study. Cases (n=2160) were from a repository of SCA in the greater Seattle area. Controls (n=2615), frequency-matched on age and sex, were from the same area. We used linear logistic regression to examine SNP associations with SCA. We performed p-min permutation tests to account for multiple comparisons within each gene. The SNP associations with corrected p-value < 0.05 were then examined in a meta-analysis of these SNP associations in nine replication studies totaling 2129 SCA cases and 23833 non-cases. Results Eight SNPs in or near 8 genes were associated with SCA risk in the discovery study, one of which was nominally significant in the replication phase (rs7737692, minor allele frequency 36%, near the LPCAT1 gene). For each copy of the minor allele, rs7737692 was associated with 13% lower SCA risk (−21% to −5%) in the discovery phase and 9% lower risk (95% CI −16% to - 1%) in the replication phase. Conclusions While none of the associations reached significance with Bonferroni correction, a common genetic variant near LPCAT1, a gene involved in the remodeling of phospholipids, was nominally associated with incident SCA risk. Further study is needed to validate this observation.

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“…L-type Ca 2+ channels (LTCCs) facilitate Ca 2+ influx during late myocyte depolarization, provoking the Ca 2+ -induced Ca 2+ release that sustains the action potential plateau and catalyzes myofilament interaction ( Bodi et al, 2005 ). LCAC superfusion has been found to dose- (1–25 μM) and time- (2–10 min) dependently reduce current density, as well as activation and inactivation kinetics of LTCCs ( Wu and Corr, 1992 ; Liu and Rosenberg, 1996 ; Ziolo et al, 2001 ). This inhibitory effect occurs regardless of intra- or extracellular LCAC delivery, is completely reversible following wash-out, and is consistent across species and preparations ( Wu and Corr, 1992 ; Liu and Rosenberg, 1996 ; Ziolo et al, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Long-Chain Acylcarnitines and Cardiac Excitation-Contraction Coupling: Links to Arrhythmias

et al. 2020

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A growing number of metabolomic studies have associated high circulating levels of the amphiphilic fatty acid metabolites, long-chain acylcarnitines (LCACs), with cardiovascular disease (CVD) risk. These studies show that plasma LCAC levels can be correlated with the stage and severity of CVD and with indices of cardiac hypertrophy and ventricular function. Complementing these recent clinical associations is an extensive body of basic research that stems mostly from the twentieth century. These works, performed in cardiomyocyte and multicellular preparations from animal and cell models, highlight stereotypical derangements in cardiac electrophysiology induced by exogenous LCAC treatment that promote arrhythmic muscle behavior. In many cases, this is coupled with acute inotropic modulation; however, whether LCACs increase or decrease contractility is inconclusive. Linked to the electromechanical alterations induced by LCAC exposure is an array of effects on cardiac excitation-contraction coupling mechanisms that overload the cardiomyocyte cytosol with Na + and Ca 2+ ions. The aim of this review is to revisit this age-old literature and collate it with recent findings to provide a pathophysiological context for the growing body of metabolomic association studies that link circulating LCACs with CVD.

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Cited by 8 publications

References 38 publications

Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines-Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-Dependent Phospholipases, and Mitochondrial Energetics Collapse

Dissecting Cellular Mechanisms of Long-Chain Acylcarnitines-Driven Cardiotoxicity: Disturbance of Calcium Homeostasis, Activation of Ca2+-Dependent Phospholipases, and Mitochondrial Energetics Collapse

Common variation in fatty acid metabolic genes and risk of incident sudden cardiac arrest

Long-Chain Acylcarnitines and Cardiac Excitation-Contraction Coupling: Links to Arrhythmias

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