Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia

Tamayo, María; Fulgencio-Covián, Alejandro; Navarro‐García, José Alberto; Val‐Blasco, Almudena; Ruiz‐Hurtado, Gema; Gil-Fernández, Marta; Martín‐Nunes, Laura; López, Juan Antonio; Desviat, Lourdes R.; Delgado, Carmen; Richard, Eva; Fernández‐Velasco, María

doi:10.1016/j.bbadis.2019.165586

Cited by 24 publications

(22 citation statements)

References 54 publications

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“…It is interesting to highlight that long-QT syndrome has also been associated with AF [ 40 , 41 ], apparently by inducing early afterdepolarization-mediated ectopic activity [ 42 ]. Moreover, cardiac dysfunction in Pcca-/-(A138T) mice was associated with lower systolic Ca 2+ release, impairment in the sarcoplasmic reticulum Ca 2+ load, and decreased Ca 2+ re-uptake by SR-Ca 2+ ATPase (SERCA2a) [ 43 ]. Notably, it has been reported that Ca 2+ -handling dysregulation can promote beat-to-beat alternation in action potential duration, favoring reentry and causing AF [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

et al. 2021

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Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10−8) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies.

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Section: Discussionmentioning

confidence: 99%

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

et al. 2021

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“…The increased expression of Pcca in the ArBu administration groups affected the impairment of systolic Ca 2+ release and to irregular diastolic Ca 2+ release, leading to cardiac and cellular contractility abnormalities. These changes were also associated with increased levels of oxidative stress in cardiomyocytes ( Tamayo et al, 2020 ). In conclusion, Trap1, Pcca, Mrps6 and Idh2 were potential biomarkers for the cardiotoxicity of ArBu.…”

Section: Resultsmentioning

confidence: 99%

Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats

et al. 2021

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Arenobufagin (ArBu), one of the main active bufadienolides of toad venom with cardiotonic effect, analgesic effect, and outstanding anti-tumor potentiality, is also a potential cardiotoxic component. In the present study, the cardiac effect of ArBu and its underlying mechanism were explored by integrating data such as heart rates, toxicokinetics, myocardial enzyme and brain natriuretic peptide (BNP) activity, pathological sections, lipidomics and proteomics. Under different doses, the cardiac effects turned out to be different. The oral dose of 60 mg/kg of ArBu sped up the heart rate. However, 120 mg/kg ArBu mainly reduced the heart rate. Over time, they all returned to normal, consisting of the trend of ArBu concentration-time curve. High concentrations of myocardial enzymes and BNP indicated that ArBu inhibited or impaired the cardiac function of rats. Pathological sections of hearts also showed that ArBu caused myocardial fiber disorder and rupture, in which the high-dose group was more serious. At the same time, serum and heart tissue lipidomics were used to explore the changes in body lipid metabolism under different doses. The data indicated a larger difference in the high-dose ArBu group. There were likewise many significant differences in the proteomics of the heart. Furthermore, a multi-layered network was used to integrate the above information to explore the potential mechanism. Finally, 4 proteins that were shown to be significantly and differentially expressed were validated by targeted proteomics using parallel reaction monitoring (PRM) analysis. Our findings indicated that ArBu behaved as a bidirectional regulation of the heart. The potential mechanism of cardiac action was revealed with the increased dose, which provided a useful reference for the safety of clinical application of ArBu.

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“…Ca 2+ is an important cation in the conversion of an electrical signal to mechanical function in the heart from beat to beat [ 1 , 88 , 93 , 118 , 126 ]. The voltage-gated L-type Ca 2+ channels (LTCCs) located in the plasma membrane are activated by depolarization of the myocyte membrane, which leads to a small amount of inward Ca 2+ flux ( I Ca ) [ 44 , 50 , 81 , 117 , 123 , 130 ]. This Ca 2+ entry through LTCCs triggers large quantities of Ca 2+ to be released from the SR via cardiac ryanodine receptor type-2 (RyR2; also called Ca 2+ -triggered SR Ca 2+ release channels) [ 9 , 84 , 93 ].…”

Section: Physiological Calcium Dynamics In the Heartmentioning

confidence: 99%

Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

McKee

Bare

2021

Pflugers Arch - Eur J Physiol

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Calcium homeostasis in the cardiomyocyte is critical to the regulation of normal cardiac function. Abnormal calcium dynamics such as altered uptake by the sarcoplasmic reticulum (SR) Ca2+-ATPase and increased diastolic SR calcium leak are involved in the development of maladaptive cardiac remodeling under pathological conditions. Ca2+/calmodulin-dependent protein kinase II-δ (CaMKIIδ) is a well-recognized key molecule in calcium dysregulation in cardiomyocytes. Elevated cellular stress is known as a common feature during pathological remodeling, and c-jun N-terminal kinase (JNK) is an important stress kinase that is activated in response to intrinsic and extrinsic stress stimuli. Our lab recently identified specific actions of JNK isoform 2 (JNK2) in CaMKIIδ expression, activation, and CaMKIIδ-dependent SR Ca2+ mishandling in the stressed heart. This review focuses on the current understanding of cardiac SR calcium handling under physiological and pathological conditions as well as the newly identified contribution of the stress kinase JNK2 in CaMKIIδ-dependent SR Ca2+ abnormal mishandling. The new findings identifying dual roles of JNK2 in CaMKIIδ expression and activation are also discussed in this review.

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Intracellular calcium mishandling leads to cardiac dysfunction and ventricular arrhythmias in a mouse model of propionic acidemia

Cited by 24 publications

References 54 publications

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats

Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

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