scholarly journals Possible Role of Interaction between PPARαand Cyclophilin D in Cardioprotection of AMPK againstIn VivoIschemia-Reperfusion in Rats

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Giselle Barreto-Torres ◽  
Sabzali Javadov
Keyword(s):  
Cardiac Function ◽  
Mitochondrial Function ◽  
Mitochondrial Permeability Transition ◽  
Synergistic Effects ◽  
Ischemia Reperfusion ◽  
Protective Effects ◽  
Simultaneous Administration ◽  
Cyclophilin D ◽  
Ptp Opening

Activated AMPK protects the heart from cardiac ischemia-reperfusion (IR) injury and is associated with inhibition of mitochondrial permeability transition pore (PTP) opening. On the other hand, pharmacological inhibition of the PTP reduces infarct size and improves cardiac function. However, it is unclear whether beneficial effects of AMPK are mediated through the PTP and, if they are not, whether simultaneous activation of AMPK and inhibition of the PTP exert synergistic protective effects against cardiac IR injury. Here, we examined the effects of the AMPK activator, A-769662 in combination with the PTP inhibitor, sanglifehrin A (SfA) onin vivocardiac IR. Cardiac dysfunction following IR injury was associated with decreased activity of the mitochondrial electron transport chain (ETC) and increased mitochondrial ROS and PTP opening. Administration of A-769662 or SfA individually upon reperfusion improved cardiac function, reduced infarction size, and inhibited ROS production and PTP opening. However, simultaneous administration of SfA and A-769662 did not provide synergistic improvement of postischemic recovery of cardiac and mitochondrial function, though both compounds disrupted IR-induced interaction between PPARαand CyP-D. In conclusion, A-769662 or SfA prevents PPARαinteraction with CyP-D, improving cardiac outcomes and increasing mitochondrial function, and simultaneous administration of the drugs does not provide synergistic effects.

Abstract 162: Influence of Age and Ischemia on Cardiac Subsarcolemmal and Interfibrillar Mitochondria in a Novel Model of Estrogen Deficiency

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra M Garvin ◽  
Nicole C Aurigemma ◽  
Donna H Korzick
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Protective Efficacy ◽  
Ischemia Reperfusion ◽  
Female Rats ◽  
Coronary Artery Ligation ◽  
Cyclophilin D ◽  
Artery Ligation ◽  
Retention Capacity ◽  
Novel Model

Altered mitochondrial respiration (MR) and calcium retention capacity (CRC) are proposed cardiac cell death mechanisms exacerbated by aging in males. The present study aimed, for the first time, to determine changes in mitochondrial subpopulation function with age and ischemia/reperfusion (I/R) injury in the female heart. A novel model to recapitulate human menopause/age interactions was used in F344 female rats ovariectomized (OVX) at 15mo and studied at 24mo (MO OVX; n=15), vs adult (6mo; n=18). MR and CRC were assessed in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria following in vivo coronary artery ligation (CAL; 31 min I and 10 min R) or sham. State 3 MR energized by either complex I (CI) or complex II (CII) substrates was selectively reduced by age in SSM (p<.02), and by I/R in IFM (p<.05). The I/R-dependent decrease in CRC was 64% (18 vs 29.5) greater in MO OVX vs. adult IFM, suggesting earlier mitochondrial permeability transition pore (MPTP) opening. At CI, but not CII, cyclosporine A (CsA) enhanced CRC 20% (103 vs 86) more in SSM and 75% (98 vs 56) more in IFM from adult compared to MO OVX, suggesting reduced protective efficacy with age and MPTP involvement. Additionally, mitochondrial cyclophilin D increases with age, while cytoplasmic RIP1 is increased with age and I/R further implicating the MPTP mechanism and link with programmed necrosis in the aged female heart. In contrast to males, our data suggest a sex-specific phenotype whereby reductions in both SSM and IFM dynamics may play an additive role in the enhanced susceptibility to I/R injury and myocardial infarction in the aged female heart, which remains the leading cause of death in older women.

Involvement of Cyclophilin D and Calcium in Isoflurane-induced Preconditioning

2015 ◽  
Vol 123 (6) ◽  
pp. 1374-1384 ◽  
Author(s):  
Geoffrey Teixeira ◽  
Pascal Chiari ◽  
Jeremy Fauconnier ◽  
Maryline Abrial ◽  
Elisabeth Couture-Lepetit ◽  
...  
Keyword(s):  
Infarct Size ◽  
Complex I ◽  
Mitochondrial Membrane ◽  
Matrix Protein ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Cyclophilin D ◽  
Wild Type ◽  
Endogenous Protection ◽  
Ptp Opening

Abstract Background The mitochondrial permeability transition pore (PTP) has been established as an important mediator of ischemia–reperfusion–induced cell death. The matrix protein cyclophilin D (CypD) is the best known regulator of PTP opening. Therefore, the authors hypothesized that isoflurane, by inhibiting the respiratory chain complex I, another regulator of PTP, might reinforce the myocardial protection afforded by CypD inhibition. Methods Adult mouse or isolated cardiomyocytes from wild-type or CypD knockout (CypD-KO) mice were subjected to ischemia or hypoxia followed by reperfusion or reoxygenation. Infarct size was assessed in vivo. Mitochondrial membrane potential and PTP opening were assessed using tetramethylrhodamine methyl ester perchlorate and calcein–cobalt fluorescence, respectively. Fluo-4 AM and rhod-2 AM staining allowed the measurement, by confocal microscopy, of Ca2+ transient and Ca2+ transfer from sarcoplasmic reticulum (SR) to mitochondria after caffeine stimulation. Results Both inhibition of CypD and isoflurane significantly reduced infarct size (−50 and −37%, respectively) and delayed PTP opening (+63% each). Their combination had no additive effect (n = 6/group). CypD-KO mice displayed endogenous protection against ischemia–reperfusion. Isoflurane depolarized the mitochondrial membrane (−28%, n = 5), decreased oxidative phosphorylation (−59%, n = 5), and blunted the caffeine-induced Ca2+ transfer from SR to mitochondria (−22%, n = 7) in the cardiomyocytes of wild-type mice. Importantly, this transfer was spontaneously decreased in the cardiomyocytes of CypD-KO mice (−25%, n = 4 to 5). Conclusions The results suggest that the partial inhibitory effect of isoflurane on respiratory complex I is insufficient to afford a synergy to CypD-induced protection. Isoflurane attenuates the Ca2+ transfer from SR to mitochondria, which is also the prominent role of CypD, and finally prevents PTP opening.

scholarly journals Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 176 ◽  
Author(s):  
George A. Porter ◽  
Gisela Beutner
Keyword(s):  
Electron Transport ◽  
Mitochondrial Function ◽  
Electron Transport Chain ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mitochondrial Protein ◽  
Cyclophilin D ◽  
Master Regulator ◽  
Transport Chain

Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia–reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD’s actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function.

scholarly journals Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

2011 ◽  
Vol 301 (1) ◽  
pp. F134-F150 ◽  
Author(s):  
Jeong Soon Park ◽  
Ratna Pasupulati ◽  
Thorsten Feldkamp ◽  
Nancy F. Roeser ◽  
Joel M. Weinberg
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Subsequent Development ◽  
Permeability Transition ◽  
Nonesterified Fatty Acid ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Wide Range

Mitochondrial matrix cyclophilin D (CyPD) is known to promote development of the mitochondrial permeability transition (MPT). Kidney proximal tubule cells are especially prone to deleterious effects of mitochondrial damage because of their dependence on oxidative mitochondrial metabolism for ATP production. To clarify the role of CyPD and the MPT in proximal tubule injury during ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R), we assessed freshly isolated tubules and in vivo injury in wild-type (WT) and Ppif−/− CyPD-null mice. Isolated mouse tubules developed a sustained, nonesterified fatty acid-mediated energetic deficit after H/R in vitro that could be substantially reversed by delipidated albumin and supplemental citric acid cycle substrates but was not modified by the absence of CyPD. Susceptibility of WT and Ppif−/− tubules to the MPT was increased by H/R but was less in normoxic and H/R Ppif−/− than WT tubules. Correction of the energetic deficit that developed during H/R strongly increased resistance to the MPT. Ppif−/− mice were resistant to I/R injury in vivo spanning a wide range of severity. The data clarify involvement of the MPT in oxygen deprivation-induced tubule cell injury by showing that the MPT does not contribute to the initial bioenergetic deficit produced by H/R but the deficit predisposes to subsequent development of the MPT, which contributes pathogenically to kidney I/R injury in vivo.

scholarly journals Tanshinone IIA combined with CsA inhibit myocardial cell apoptosis induced by renal ischemia-reperfusion injury in obese rats

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
He Tai ◽  
Xiao-lin Jiang ◽  
Zhi-ming Lan ◽  
Yue Li ◽  
Liang Kong ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Abdominal Cavity ◽  
Myocardial Cell ◽  
Renal Ischemia ◽  
Tanshinone Iia ◽  
Obese Rats

Abstract Background Acute myocardial injury (AMI), which is induced by renal ischemia-reperfusion (IR), is a significant cause of acute kidney injury (AKI)-related associated death. Obesity increases the severity and frequency of AMI and AKI. Tanshinone IIA (TIIA) combined with cyclosporine A (CsA) pretreatment was used to alleviate myocardial cell apoptosis induced by renal IR, and to determine whether TIIA combined with CsA would attenuate myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats. Methods Male rates were fed a high fat diet for 8 weeks to generate obesity. AKI was induced by 30 min of kidney ischemia followed 24 h of reperfusion. Obese rats were given TIIA (10 mg/kg·d) for 2 weeks and CsA (5 mg/kg) 30 min before renal IR. After 24 h of reperfusion, the rats were anaesthetized, the blood were fetched from the abdominal aorta and kidney were fetched from abdominal cavity, then related indicators were examined. Results TIIA combined with CsA can alleviate the pathohistological injury and apoptosis induced by renal IR in myocardial cells. TIIA combined with CsA improved cardiac function after renal ischemia (30 min)-reperfusion (24 h) in obese rats. At the same time, TIIA combined with CsA improved mitochondrial function. Abnormal function of mitochondria was supported by decreases in respiration controlling rate (RCR), intracellular adenosine triphosphate (ATP), oxygen consumption rate, and mitochondrial membrane potential (MMP), and increases in mitochondrial reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA damage, and mitochondrial respiratory chain complex enzymes. The injury of mitochondrial dynamic function was assessed by decrease in dynamin-related protein 1 (Drp1), and increases in mitofusin1/2 (Mfn1/2), and mitochondrial biogenesis injury was assessed by decreases in PPARγ coactivator-1-α (PGC-1), nucleo respiratory factor1 (Nrf1), and transcription factor A of mitochondrial (TFam). Conclusion We used isolated mitochondria from rat myocardial tissues to demonstrate that myocardial mitochondrial dysfunction occurred along with renal IR to induce myocardial cell apoptosis; obesity aggravated apoptosis. TIIA combined with CsA attenuated myocardial cell apoptosis by modulating mitochondrial function through the PI3K/Akt/Bad pathway in obese rats.

scholarly journals Propofol attenuates lung ischemia/reperfusion injury though the involvement of the MALAT1/microRNA-144/GSK3β axis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jian-Ping Zhang ◽  
Wei-Jing Zhang ◽  
Miao Yang ◽  
Hua Fang
Keyword(s):  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Glycogen Synthase ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Loss Of Function

Abstract Background Propofol, an intravenous anesthetic, was proven to protect against lung ischemia/reperfusion (I/R) injury. However, the detailed mechanism of Propofol in lung I/R injury is still elusive. This study was designed to explore the therapeutic effects of Propofol, both in vivo and in vitro, on lung I/R injury and the underlying mechanisms related to metastasis-associated lung adenocarcinoma transcript 1 (MALAT1)/microRNA-144 (miR-144)/glycogen synthase kinase-3β (GSK3β). Methods C57BL/6 mice were used to establish a lung I/R injury model while pulmonary microvascular endothelial cells (PMVECs) were constructed as hypoxia/reperfusion (H/R) cellular model, both of which were performed with Propofol treatment. Gain- or loss-of-function approaches were subsequently employed, followed by observation of cell apoptosis in lung tissues and evaluation of proliferative and apoptotic capabilities in H/R cells. Meanwhile, the inflammatory factors, autophagosomes, and autophagy-related proteins were measured. Results Our experimental data revealed that Propofol treatment could decrease the elevated expression of MALAT1 following I/R injury or H/R induction, indicating its protection against lung I/R injury. Additionally, overexpressing MALAT1 or GSK3β promoted the activation of autophagosomes, proinflammatory factor release, and cell apoptosis, suggesting that overexpressing MALAT1 or GSK3β may reverse the protective effects of Propofol against lung I/R injury. MALAT1 was identified to negatively regulate miR-144 to upregulate the GSK3β expression. Conclusion Overall, our study demonstrated that Propofol played a protective role in lung I/R injury by suppressing autophagy and decreasing release of inflammatory factors, with the possible involvement of the MALAT1/miR-144/GSK3β axis.

Stress-induced opening of the permeability transition pore in the dystrophin-deficient heart is attenuated by acute treatment with sildenafil

2011 ◽  
Vol 300 (1) ◽  
pp. H144-H153 ◽  
Author(s):  
Alexis Ascah ◽  
Maya Khairallah ◽  
Frédéric Daussin ◽  
Céline Bourcier-Lucas ◽  
Richard Godin ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Contractile Function ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Clinical Signs ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mdx Mice ◽  
Uptake Velocity ◽  
Ptp Opening

Susceptibility of cardiomyocytes to stress-induced damage has been implicated in the development of cardiomyopathy in Duchenne muscular dystrophy, a disease caused by the lack of the cytoskeletal protein dystrophin in which heart failure is frequent. However, the factors underlying the disease progression are unclear and treatments are limited. Here, we tested the hypothesis of a greater susceptibility to the opening of the mitochondrial permeability transition pore (PTP) in hearts from young dystrophic ( mdx) mice (before the development of overt cardiomyopathy) when subjected to a stress protocol and determined whether the prevention of a PTP opening is involved in the cardioprotective effect of sildenafil, which we have previously reported in mdx mice. Using the 2-deoxy-[3H]glucose method to quantify the PTP opening in ex vivo perfused hearts, we demonstrate that when compared with those of controls, the hearts from young mdx mice subjected to ischemia-reperfusion (I/R) display an excessive PTP opening as well as enhanced activation of cell death signaling, mitochondrial oxidative stress, cardiomyocyte damage, and poorer recovery of contractile function. Functional analyses in permeabilized cardiac fibers from nonischemic hearts revealed that in vitro mitochondria from mdx hearts display normal respiratory function and reactive oxygen species handling, but enhanced Ca2+ uptake velocity and premature opening of the PTP, which may predispose to I/R-induced injury. The administration of a single dose of sildenafil to mdx mice before I/R prevented excessive PTP opening and its downstream consequences and reduced tissue Ca2+ levels. Furthermore, mitochondrial Ca2+ uptake velocity was reduced following sildenafil treatment. In conclusion, beyond our documentation that an increased susceptibility to the opening of the mitochondrial PTP in the mdx heart occurs well before clinical signs of overt cardiomyopathy, our results demonstrate that sildenafil, which is already administered in other pediatric populations and is reported safe and well tolerated, provides efficient protection against this deleterious event, likely by reducing cellular Ca2+ loading and mitochondrial Ca2+ uptake.

scholarly journals Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion

2008 ◽  
Vol 295 (4) ◽  
pp. G823-G832 ◽  
Author(s):  
Zhi Zhong ◽  
Venkat K. Ramshesh ◽  
Hasibur Rehman ◽  
Robert T. Currin ◽  
Vijayalakshmi Sridharan ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Oxygen Sensing ◽  
Ischemia Reperfusion ◽  
Multiphoton Microscopy ◽  
Specific Inhibitor ◽  
Permeability Transition ◽  
Heme Oxygenase 1 ◽  
Mitochondrial Depolarization ◽  
Signal Cascade

The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1α and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to ∼70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 μmol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1.

Abstract 47: Loss of the Cardio Protection Inferred by S-nitrosylation of GRK2 At Cysteine 340 Leads to Decreased Cardiac Performance and a Hypertensive Phenotype With Aging

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Christopher J Traynham ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
Walter Koch
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Ischemia Reperfusion ◽  
Cardiac Performance ◽  
Heart Weight ◽  
Cardiac Phenotype ◽  
Cardio Protection ◽  
G Protein Coupled ◽  
Global Population

In the next 35 years, the global population of individuals above 60 years of age will double to approximately 2 billion. In the aged population, cardiovascular diseases are known to occur at a higher prevalence ultimately leading to increased mortality. G protein-coupled receptors (GPCRs) have been identified as vital regulators of cardiac function. GPCR kinases (GRKs) are important in cardiac GPCR regulation through desensitization of these receptors. GRK2 is highly expressed in the heart, and has been widely characterized due to its upregulation in heart failure. Studies from our lab have shown that elevated GRK2 levels in ischemia-reperfusion (I/R) injury result in a pro-death phenotype. Interestingly, cardio-protection can be inferred via S-nitrosylation of GRK2 at cysteine 340. Further, we have generated a knock-in GRK2 340S mouse, in which cysteine 340 was mutated to block dynamic GRK2 S-nitrosylation. GRK2 340S mice are more susceptible to I/R injury. Given that GRK2 340S mice are more susceptible to oxidative stress, and there is a nitroso-redox imbalance in senescence, it is possible that these mice are more likely to exhibit decreased cardiac performance as they age. Therefore, we hypothesize that with age GRK2 340S knockin mice will develop an overall worsened cardiac phenotype compared to control wild-type (WT) mice. To test this hypothesis, 340S and WT mice were aged for a year, and cardiac function was evaluated via echocardiography. Aged 340S mice exhibited significantly decreased ejection fraction and fraction shortening relative to aged WT controls. Prior to tissue harvesting, in-vivo hemodynamics was conducted via Millar catheterization. At baseline, aged 340S mice exhibited increased systolic blood pressure compared to aged WT mice. At the conclusion of this protocol, mice were sacrificed and heart weight (HW), body weight (BW), and tibia length (TL) measured to evaluate cardiac hypertrophy. Aged 340S mice exhibited significantly increased HW/BW and HW/TL ratios, indicative of cardiac hypertrophy, relative to aged WT controls. Taken together, these data suggest that with age, loss of the cardio protection inferred by S-nitrosylation of GRK2 at leads to decreased cardiac performance, and an overall worsened cardiac phenotype.

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