Involvement of mitochondrial permeability transition pore (mPTP) in cardiac arrhythmias: Evidence from cyclophilin D knockout mice

Abstract

In the present study, we have used a genetic mouse model that lacks cyclophilin D (CypD KO) to assess the cardioprotective effect of mitochondrial permeability transition pore (mPTP) inhibition on Ca2+ waves and Ca2+ alternans at the single cell level, and cardiac arrhythmias in whole-heart preparations. The protonophore carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) caused mitochondrial membrane potential depolarization to the same extent in cardiomyocytes from both WT and CypD KO mice, however, cardiomyocytes from CypD KO mice exhibited significantly less mPTP opening than cardiomyocytes from WT mice (p < 0.05). Consistent with these results, FCCP caused significant increases in CaW rate in WT cardiomyocytes (p < 0.05) but not in CypD KO cardiomyocytes. Furthermore, the incidence of Ca2+ alternans after treatment with FCCP and programmed stimulation was significantly higher in WT cardiomyocytes (11 of 13), than in WT cardiomyocytes treated with CsA (2 of 8; p < 0.05) or CypD KO cardiomyocytes (2 of 10; p < 0.01). (Pseudo-)Lead II ECGs were recorded from ex vivo hearts. We observed ST-T-wave alternans (a precursor of lethal arrhythmias) in 5 of 7 WT hearts. ST-T-wave alternans was not seen in CypD KO hearts (n=5) and in only 1 of 6 WT hearts treated with CsA. Consistent with these results, WT hearts exhibited a significantly higher average arrhythmia score than CypD KO (p <0.01) hearts subjected to FCCP treatment or chemical ischemia-reperfusion (p < 0.01). In conclusion, CypD deficiency-induced mPTP inhibition attenuates CaWs and Ca2+ alternans during mitochondrial depolarization, and thereby protects against arrhythmogenesis in the heart.

Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain

“…Knockout of cyclophilin D has been shown to stabilize mitochondrial function and mitigate the cognitive impairment in old AD transgenic mice (Du et al, 2008(Du et al, , 2011(Du et al, , 2014. Moreover, KO of CypD can inhibit mPTP opening and attenuate arrhythmogenesis in the heart of rats (Gordan et al, 2016). Consistently, we showed that KO of CypD could attenuate the sevoflurane anesthesia-induced mitochondrial dysfunction, impairment of neurogenesis, and cognitive impairment in vitro and in vivo.…”

“…The expression of CypD was elevated in brain tissues of Alzheimer's disease (AD) transgenic mice (Du et al, 2008(Du et al, , 2011(Du et al, , 2014, which promotes AD neuropathogenesis (Wang et al, 2009;Zhu et al, 2013;Adiele and Adiele, 2016). Knockout (KO) of CypD stabilized mitochondrial function (Du et al, 2008(Du et al, , 2011(Du et al, , 2014Gainutdinov et al, 2015;Gordan et al, 2016;Sun and Jacobs, 2016), decreased threshold of mPTP formation, and improved cognitive function in old AD transgenic mice (Du et al, 2008(Du et al, , 2011(Du et al, , 2014. However, the role of CypD in the developmental anesthesia neurotoxicity remains largely to be determined.…”

Adaptive respiratory response of rat pancreatic acinar cells to mitochondrial membrane depolarization

“…FCCP was shown to cause the opening of mitochondrial permeability transition pore in cardiomyocytes [19]. In the present study, we did not investigate the potential role of the pore in a timedependent decrease of uncoupled respiration.…”

Impact of Music on Sport Intensity (Allegro) and on Levels of Left Ventricular Myocardial Damage in Wistar Rats

“…High-intensity exercise will improve Cyclic Adenosine Monophosphate (cAMP). Protein Kinase A (PKA) send signal toward target proteins such as L-Type Ca Chanel (LTCC) to Sarcoplasmic Reticulum (SR) which plays a phospolamban role for contraction of Troponin C, I and T. In addition, it also binds ions to increase heart rate (Gordan et al, 2016). Heart rate increased will trigger blood pressure and cause parallel sarcomeres increased, resulting in widened cells that result in increased left ventricular wall thickness without reducing organ size at the time of diastole with left concentric development resulting in hypertrophy (Fernandes et al, 2011).…”