Journal of molecular and cellular cardiology plus最新文献

Background

Methods

Results

Conclusions

Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the calcium (Ca²⁺) release channel ryanodine receptor (RyR2) and its accessory proteins. These mutations make the channel leaky, resulting in Ca²⁺-dependent arrhythmias. Besides arrhythmias, CPVT hearts typically lack structural cardiac remodeling, a characteristic often observed in other cardiac conditions (heart failure, prediabetes) also marked by RyR2 leak. Recent studies suggest that mitochondria are able to accommodate more Ca²⁺ influx to inhibit arrhythmias in CPVT. Thus, we hypothesize that CPVT mitochondria can absorb diastolic Ca²⁺ to protect the heart from cardiac remodeling.

Methods and results

The Mitochondrial Ca²⁺ uniporter (MCU), the main mitochondrial Ca²⁺ uptake protein, was conditionally knocked out in a CPVT model of calsequestrin 2 (CASQ2) KO. In vivo cardiac function was impaired in the CASQ2^−/−-MCU^CKO model as assessed by echocardiography. Cardiac dilation and cellular hypertrophy were also observed in the CASQ2^−/−-MCU^CKO hearts. Live-cell imaging identified altered Ca²⁺ handling and increased oxidative stress in CASQ2^−/−-MCU^CKO myocytes. The activation status of Ca²⁺-dependent remodeling pathways (CaMKII, Calcineurin) was not altered in the CASQ2^−/−-MCU^CKO model. RNAseq identified changes in the transcriptome of the CASQ2^−/−-MCU^CKO hearts, distinct from the classic cardiac remodeling program of fetal gene re-expression.

Conclusions

We present genetic evidence that mitochondria play a protective role in CPVT. MCU-dependent Ca²⁺ uptake is crucial for preventing pathological cardiac remodeling in CPVT.

Background and aims

Cadherins are adhesion proteins, and their dysregulation may result in the development of atherosclerosis, plaque rupture, or lesions of the vascular wall. The aim of the present study was to detect the associations of cadherins-P, −E, and H, with atherosclerosis and pathological cardiovascular conditions.

Methods and results

The present study with 3-year follow up evaluated atherosclerosis and fasting levels of P-, E-, and H-cadherins in the serum samples of 214 patients in a hospital setting. Coronary lesions were assessed by coronary angiography as Gensini score. Serum proteomic profiling was performed using antibody microarrays. The contents of P-, E-, and H-cadherins in the serum were measured using indirect ELISA. High levels of P- and E-cadherins and low levels of H-cadherin were associated with severity of atherosclerosis. High levels of P- and E-cadherins were associated with higher incidence of nonfatal cardiovascular outcomes. E-cadherin was associated with higher incidence of recurrent revascularization during 3 year follow-up. The results of Spearman rank correlation analysis revealed various associations of the three cadherins with lipid, endothelial, and metabolic biomarkers.

Conclusions

The data indicated that classical and atypical cadherins were associated with atherosclerosis progression. Elevated levels of P-cadherin were associated with coronary atherosclerosis. The data indicated that various lipid, endothelial, and metabolic biomarkers may influence the levels of cadherins. Thus, P-, E-, and H-cadherins may be promising markers for the assessment of cardiovascular risk.

Dravet Syndrome (DS) is a pediatric-onset epilepsy with an elevated risk of Sudden Unexpected Death in Epilepsy (SUDEP). Most individuals with DS possess mutations in the voltage-gated sodium channel gene Scn1a, expressed in both the brain and heart. Previously, mutations in Scn1a have been linked to arrhythmia. We used a Scn1a^−/+ DS mouse model to investigate changes to cardiac mitochondrial function that may underlie arrhythmias and SUDEP. We detected significant alterations in mitochondrial bioenergetics that were sex-specific. Mitochondria from male Scn1a^−/+ hearts had deficits in maximal (p = 0.02) and Complex II-linked respiration (p = 0.03). Male Scn1a^−/+ mice were also more susceptible to cardiac arrhythmias under increased workload. When isolated cardiomyocytes were subjected to diamide, cardiomyocytes from male Scn1a^−/+ hearts were less resistant to thiol oxidation. They had decreased survivability compared to Scn1a^+/+ (p = 0.02) despite no whole-heart differences. Lastly, there were no changes in mitochondrial ROS production between DS and wild-type mitochondria at basal conditions, but Scn1a^−/+ mitochondria accumulated more ROS during hypoxia/reperfusion. This study determines novel sex-linked differences in mitochondrial and antioxidant function in Scn1a-linked DS. Importantly, we found that male Scn1a^−/+ mice are more susceptible to cardiac arrhythmias than female Scn1a^−/+ mice. When developing new therapeutics to address SUDEP risk in DS, sex should be considered.