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1.  Angiotensin II-Superoxide Signaling and Arterial Baroreceptor Function in Type-1 Diabetes Mellitus 
Journal of diabetes & metabolism  2013;Suppl 12:1-6.
Diabetes is a major world health problem. Growing evidence from both clinical trials and animal experiments has clearly confirmed that arterial baroreflex dysfunction is a feature of type 1 diabetes, which links to prognosis and mortality of the type 1 diabetic patients. The arterial baroreflex normally regulates the blood pressure and heart rate through sensing changes of arterial vascular tension by the arterial baroreceptors in the aortic arch and carotid sinus. The aortic baroreceptor neuron located in the nodose ganglia is a primary afferent component of the arterial baroreflex. The functional changes of these neurons are involved in the arterial baroreflex dysfunction in the type 1 diabetes. Type 1 diabetes causes the overexpression and hyperactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and further reduces cell excitability of the aortic baroreceptor neurons. The alterations of the HCN channels are regulated by angiotensin II-NADPH oxidase-superoxide signaling in the aortic baroreceptor neurons. From the present review, we can understand the possible mechanisms responsible for the attenuated arterial baroreflex in the type 1 diabetes. These findings are beneficial for improving quality of life and prognosis in patients with the type 1 diabetes mellitus.
doi:10.4172/2155-6156.S12-001
PMCID: PMC3932051  PMID: 24567847
Baroreflex; Baroreceptor; Ion channels; Angiotensin II; Superoxide; Diabetes
2.  2-(1-Benzo­thio­phen-2-yl)-4H-1,3,4-oxa­diazin-5(6H)-one 
In the title compound, C11H8N2O2S, the oxadiazinone ring is nearly planar [maximum deviation = 0.016 (4) Å], and is approximately coplanar with the benzo­thio­phene ring system [dihedral angle = 3.1 (5)°]. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds, forming chains running along the b-axis direction.
doi:10.1107/S1600536813033291
PMCID: PMC3914084  PMID: 24526987
3.  Elevated angiotensin II in rat nodose ganglia primes diabetes-blunted arterial baroreflex sensitivity: involvement of NADPH oxidase-derived superoxide 
Journal of diabetes & metabolism  2011;2(6):1000135.
Clinical trials and experimental animal studies have confirmed the contribution of arterial baroreflex impairment in causing excess morbidity and mortality in type-1 diabetes. Our previous study has shown that angiotensin II (Ang II)-NADPH oxidase-superoxide signaling is associated with the reduced cell excitability in the aortic baroreceptor neurons (a primary afferent limb of the arterial baroreflex) from diabetic rats. In this study, we examined whether above-mentioned signaling might contribute to the blunted baroreflex sensitivity in streptozotocin-induced diabetic rats. Using Ang II 125I radioimmunoassay and lucigenin chemiluminescence method, we found Ang II concentration, NADPH oxidase activity, and superoxide production in the nodose ganglia were enhanced in diabetic rats, compared to sham rats. As an index of the arterial baroreflex sensitivity, the reflex decreases in blood pressure and heart rate evoked by unilateral steady-frequency aortic depressor nerve stimulation were attenuated in diabetic rats. Local microinjection (50 nl) of losartan (an AT1 receptor antagonist, 1 nmol), apocynin (a NADPH oxidase inhibitor, 1 nmol), and tempol (a superoxide dismutase mimetic, 10 nmol) into the nodose ganglia significantly improved the arterial baroreflex sensitivity in diabetic rats. In addition, these three chemicals also normalized exogenous Ang II-attenuated arterial baroreflex sensitivity in sham rats. These results indicate that overactivation of the Ang II-NADPH oxidase-superoxide signal pathway in the nodose ganglia contributes to the blunted baroreflex sensitivity in diabetes.
doi:10.4172/2155-6156.1000135
PMCID: PMC3269316  PMID: 22308229
Angiotensin II; Baroreflex; Diabetes; NADPH oxidase; Superoxide
4.  Reduced expression and activation of voltage-gated sodium channels contributes to blunted baroreflex sensitivity in heart failure rats 
Journal of neuroscience research  2010;88(15):3337-3349.
Voltage-gated sodium (Nav) channels are responsible for initiation and propagation of action potential in the neurons. To explore the mechanisms for chronic heart failure (CHF)-induced baroreflex dysfunction, we measured the expression and current density of Nav channel subunits (Nav1.7, Nav1.8, and Nav1.9) in the aortic baroreceptor neurons and investigated the role of Nav channels on aortic baroreceptor neuron excitability and baroreflex sensitivity in sham and CHF rats. CHF was induced by left coronary artery ligation. The development of CHF (6–8 weeks after the coronary ligation) was confirmed by hemodynamic and morphological characteristics. Immunofluorescent data indicated that Nav1.7 was expressed in A-type (myelinated) and C-type (unmyelinated) nodose neurons but Nav1.8 and Nav1.9 were expressed only in C-type nodose neurons. Real-time RT-PCR and western blot data showed that CHF reduced mRNA and protein expression levels of Nav channels in nodose neurons. In addition, using the whole cell patch-clamp technique, we found that Nav current density and cell excitability of the aortic baroreceptor neurons were lower in CHF rats than that in sham rats. Aortic baroreflex sensitivity was blunted in anesthetized CHF rats, compared with that in sham rats. Furthermore, Nav channel activator (rATX II, 100 nM) significantly enhanced Nav current density and cell excitability of aortic baroreceptor neurons and improved aortic baroreflex sensitivity in CHF rats. These results suggest that reduced expression and activation of the Nav channels is involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in CHF state.
doi:10.1002/jnr.22483
PMCID: PMC2953570  PMID: 20857502
Aortic baroreceptor neuron; Baroreflex; Heart failure; Sodium channel
5.  Dimethyl 3,3′-(phenyl­methyl­ene)bis­(1H-indole-2-carboxyl­ate) 
In the title compound, C27H22N2O4, the two indole ring systems are approximately perpendicular to each other, with a dihedral angle of 84.5 (5)° between their planes; the benzene ring is twisted with respect to the two indole ring systems at angles of 78.5 (5) and 86.5 (3)°. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds, weak C—H⋯O and C—H⋯N hydrogen bonds, and C—H⋯π inter­actions into a three-dimensional supra­molecular architecture.
doi:10.1107/S1600536813024471
PMCID: PMC3790385  PMID: 24098207
6.  EFFECT OF AT1 RECEPTOR BLOCKADE ON INTERMITTENT HYPOXIA-INDUCED ENDOTHELIAL DYSFUNCTION 
Chronic intermittent hypoxia (CIH) raises arterial pressure, impairs vasodilator responsiveness, and increases circulating angiotensin II (Ang II); however, the role of Ang II in CIH-induced vascular dysfunction is unknown. Rats were exposed to CIH or room air (NORM), and a subset of these animals was treated with losartan (Los) during the exposure period. After 28 days, vasodilatory responses to acetylcholine or nitroprusside were measured in isolated gracilis arteries. Superoxide levels and Ang II receptor protein expression were measured in saphenous arteries. After 28 days, arterial pressure was increased and acetylcholine-induced vasodilation was blunted in CIH vs. NORM, and this was prevented by Los. Responses to nitroprusside and superoxide levels did not differ between CIH and NORM. Expression of AT2R was decreased and the AT1R:AT2R ratio was increased in CIH vs. NORM, but this was unaffected by Los. These results indicate that the blood pressure elevation and endothelial dysfunction associated with CIH is dependent, at least in part, on RAS signaling.
doi:10.1016/j.resp.2012.05.025
PMCID: PMC3409315  PMID: 22728949
Intermittent hypoxia; Endothelial function; Angiotensin II
7.  Tetra­phenyl­phospho­nium [μ3-(4-methyl­phen­yl)tellurolato]tris­[tetra­carbonyl­iron(0)] 
In the anion of the title compound, (C24H20P)[Fe3(C7H7Te)(CO)12], each Fe0 atom is coordinated by four CO ligands and a Te atom, resulting in a trigonal–bipyramidal coordination environment. The Te atom is coordinated by a 4-methyl­phenyl group and the Fe0 atoms in a distorted tetra­hedral geometry. The average Te—Fe bond length is 2.574 (4) Å.
doi:10.1107/S1600536813013056
PMCID: PMC3684888  PMID: 23794990
8.  Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells 
BMC Neuroscience  2012;13:129.
Background
The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108-15 cells.
Results
Whole-cell patch-clamp results showed that differentiation (9 days) didn’t change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential.
Conclusion
Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation.
doi:10.1186/1471-2202-13-129
PMCID: PMC3502467  PMID: 23095258
Action potential; Na+ channel; NG108-15 cell; Patch clamp; Single-cell real-time PCR; Western blot
9.  N-[(2S)-2-Chloro­propano­yl]glycine 
The title compound, C5H8ClNO3, was prepared by the nucleophilic substitution reaction of (2S)-2-chloro­propanoyl chloride with glycine. The acetate group forms a dihedral angle of 84.6 (1)° with the mean plane of the C—NH—C=O fragment. In the crystal, the molecules are linked by N—H⋯O and O—H⋯O hydrogen bonds, generating a three-dimensional network, which consolidates the crystal packing.
doi:10.1107/S1600536812036720
PMCID: PMC3435838  PMID: 22969684
10.  Diethyl 3,3′-(phenyl­methyl­ene)bis­(1H-indole-2-carboxyl­ate) 
In the title compound, C29H26N2O4, the benzene ring is twisted by 73.5 (5) and 84.9 (3)° with respect to the mean planes of the two indole ring systems; the mean planes of the indole ring systems are oriented at a dihedral angle of 82.0 (5)°. In the crystal, mol­ecules are linked by pairs of N—H⋯O hydrogen bonds into chains.
doi:10.1107/S1600536812036239
PMCID: PMC3435799  PMID: 22969645
11.  Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles: involvement of superoxide 
European journal of pharmacology  2010;650(1):328-334.
Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Approximately 40% gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via the superoxide over-production and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
doi:10.1016/j.ejphar.2010.10.037
PMCID: PMC3008320  PMID: 21036124
Infarct size; Ischemia-reperfusion injury; Mitochondria; Superoxide; Tourniquet
12.  Ethyl 8-chloro-1-cyclo­propyl-6,7-difluoro-4-oxo-1,4-dihydro­quinoline-3-carboxyl­ate 
In the mol­ecule of the title compound, C15H12ClF2NO3, the quinoline ring system is not planar, the dihedral angle between the pyridine and benzene rings being 3.55 (8)°. In the crystal, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into layers parallel to (101).
doi:10.1107/S160053681104205X
PMCID: PMC3247378  PMID: 22219996
13.  6-Benzyl-6,7-dihydro-5H-pyrrolo­[3,4-b]pyridine-5,7-dione 
In the title compound, C14H10N2O2, the dihedral angle between the heterocyclic ring system and the phenyl ring is 45.8 (5)°. Weak inter­molecular C—H⋯N hydrogen bonding is present in the crystal structure.
doi:10.1107/S1600536811041006
PMCID: PMC3247312  PMID: 22219930
14.  CHRONIC INTERMITTENT HYPOXIA AUGMENTS CHEMOREFLEX CONTROL OF SYMPATHETIC ACTIVITY: ROLE OF THE ANGIOTENSIN II TYPE 1 RECEPTOR 
Chronic exposure to intermittent hypoxia (CIH) increases carotid sinus nerve activity in normoxia and in response to acute hypoxia. We hypothesized that CIH augments basal and chemoreflex-stimulated sympathetic outflow through an angiotensin receptor-dependent mechanism. Rats were exposed to CIH for 28 days: a subset was treated with losartan. Then, lumbar sympathetic activity was recorded under anesthesia during 20-second apneas, isocapnic hypoxia, and potassium cyanide. We measured carotid body superoxide production and expression of angiotensin II type-1 receptor, neuronal nitric oxide synthase, and NADPH oxidase. Sympathetic activity was higher in CIH vs. control rats at baseline, during apneas and isocapnic hypoxia, but not cyanide. Carotid body superoxide production and expression of angiotensin II type 1 receptor and gp91phox subunit of NADPH oxidase were elevated in CIH rats, whereas expression of neuronal nitric oxide synthase was reduced. None of these differences were evident in animals treated with losartan. CIH-induced augmentation of chemoreflex sensitivity occurs, at least in part, via the renin-angiotensin system.
doi:10.1016/j.resp.2010.02.003
PMCID: PMC2846996  PMID: 20153844
chemoreceptors; angiotensin II; superoxide; angiotensin antagonist; oxidative stress
15.  [2-Cyclo­propyl-4-(4-fluoro­phenyl)quinolin-3-yl]methanol 
The title compound, C19H16FNO, crystallizes with two independent mol­ecules in the asymmetric unit. In the two mol­ecules, the dihedral angles between the benzene and quinoline rings are 72.6 (5) and 76.2 (5)°, between the cyclo­propane and quinoline rings they are 65.2 (5) and 66.0 (5)°, and between the benzene and cyclo­propane rings they are 25.9 (5) and 33.9 (5)°. There are inter­molecular O—H⋯O, O—H⋯N and C—H⋯O hydrogen bonds, as well as intra­molecular C—H⋯O hydrogen bonds, which may be effective in stabilizing the crystal structure.
doi:10.1107/S1600536810043588
PMCID: PMC3009308  PMID: 21589152
16.  Genetic variation and evolutionary demography of Fenneropenaeus chinensis populations, as revealed by the analysis of mitochondrial control region sequences 
Genetics and Molecular Biology  2010;33(2):379-389.
Genetic variation and evolutionary demography of the shrimp Fenneropenaeus chinensis were investigated using sequence data of the complete mitochondrial control region (CR). Fragments of 993 bp of the CR were sequenced for 93 individuals from five localities over most of the species' range in the Yellow Sea and the Bohai Sea. There were 84 variable sites defining 68 haplotypes. Haplotype diversity levels were very high (0.95 ± 0.03-0.99 ± 0.02) in F. chinensis populations, whereas those of nucleotide diversity were moderate to low (0.66 ± 0.36%-0.84 ± 0.46%). Analysis of molecular variance and conventional population statistics (FST ) revealed no significant genetic structure throughout the range of F. chinensis. Mismatch distribution, estimates of population parameters and neutrality tests revealed that the significant fluctuations and shallow coalescence of mtDNA genealogies observed were coincident with estimated demographic parameters and neutrality tests, in implying important past-population size fluctuations or range expansion. Isolation with Migration (IM) coalescence results suggest that F. chinensis, distributed along the coasts of northern China and the Korean Peninsula (about 1000 km apart), diverged recently, the estimated time-split being 12,800 (7,400-18,600) years ago.
doi:10.1590/S1415-47572010005000019
PMCID: PMC3036872  PMID: 21637498
Fenneropenaeus chinensis; mtDNA; isolation with migration (IM) coalescence; historical demography; population expansion
17.  Role of CuZn superoxide dismutase on carotid body function in heart failure rabbits 
Cardiovascular Research  2008;81(4):678-685.
Aims
Peripheral chemoreflex sensitivity is potentiated in both clinical and experimental chronic heart failure (CHF). NADPH oxidase-derived superoxide mediates angiotensin II (Ang II)-enhanced carotid body (CB) chemoreceptor sensitivity in CHF rabbits, and tempol, the superoxide dismutase (SOD) mimetic, inhibits this Ang II- and CHF-enhanced superoxide anion effect. Here we investigated the role of cytoplasmic SOD [CuZn superoxide dismutase (CuZnSOD)] in the CB on chemoreceptor activity and function in CHF rabbits.
Methods and results
CuZnSOD protein expression was decreased in CBs from CHF rabbits vs. sham (P < 0.05). Adenoviral CuZnSOD (Ad CuZnSOD) gene transfer to the CBs increased CuZnSOD protein expression and significantly reduced the baseline renal sympathetic nerve activity (RSNA) and the response of RSNA to hypoxia in the CHF rabbits (P < 0.05). Single-fibre discharge from CB chemoafferents during normoxia (baseline, at ∼100 mmHg PO2) and in response to hypoxia were enhanced in CHF vs. sham rabbits (P < 0.05). Ad CuZnSOD decreased the baseline discharge (7.6 ± 1.3 vs. 12.6 ± 1.7 imp/s at ∼100 mmHg PO2) and the response to hypoxia (22.4 ± 1.6 vs. 32.3 ± 1.2 imp/s at ∼40 mmHg PO2, P < 0.05) in CHF rabbits. Ad CuZnSOD also normalized the blunted outward K+ current (IK) in CB glomus cells from CHF rabbits (369 ± 14 vs. 565 ± 31 pA/pF at +70 mV, P < 0.05). In addition, Ad CuZnSOD reduced the elevation of superoxide level in CBs from CHF rabbits.
Conclusion
Downregulation of CuZnSOD in the CB contributes to the enhanced activity of CB chemoreceptors and chemoreflex function in CHF rabbits.
doi:10.1093/cvr/cvn350
PMCID: PMC2642603  PMID: 19091790
Superoxide dismutase; Adenoviral vector; Carotid body; Sympathetic nerve activity; Chemoreceptor; Glomus cell; Chronic heart failure
18.  NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits 
Cardiovascular research  2007;75(3):546-554.
Objective:
A previous study from this laboratory showed that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin II type 1 (AT1) receptor in the carotid body (CB) are involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang II in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang II in CHF rabbits.
Methods and results:
By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 μM (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (Δ-12.5 ± 0.8 and Δ-12.8 ± 0.9 imp/s at 40.7 ± 2.3 mm Hg of PO2, and Δ-5.6 ± 0.5 and Δ-5.3 ± 0.4 imp/s at 60.2 ± 3.1 mm Hg of PO2, p<0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (Δ-13.6 ± 1.1 and Δ-13.7 ± 0.9 imp/s at 40.9 ± 3.1 mm Hg of PO2, and Δ-6.7 ± 1.2 and Δ-6.6 ± 0.8 imp/s at 59.8 ± 3.5 mm Hg of PO2, p<0.05). In addition, mRNA and protein expressions of NADPH oxidase components (gp91phox, p40phox and p47phox) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhanced superoxide anion production.
Conclusions:
These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang II in CHF rabbits occurs via a NADPH oxidase-superoxide signaling pathway.
doi:10.1016/j.cardiores.2007.04.006
PMCID: PMC2062532  PMID: 17499230
Angiotensin; Reactive oxygen species; autonomic nervous system; chemoreceptor; heart failure
19.  CAROTID BODY FUNCTION IN HEART FAILURE 
In this review, we summarize the present state of knowledge of the functional characteristics of the carotid body (CB) chemoreflex with respect to control of sympathetic nerve activity (SNA) in chronic heart failure (CHF). Evidence from both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in SNA. This adaptive change derives from altered function at the level of both the afferent and central nervous system (CNS) pathways of the reflex arc. At the level of the CB, an elevation in basal afferent discharge occurs under normoxic conditions in CHF rabbits, and the discharge responsiveness to hypoxia is enhanced. Outward voltage-gated K+ currents (IK) are suppressed in CB glomus cells from CHF rabbits, and their sensitivity to hypoxic inhibition is enhanced. These changes in IK derive partly from downregulation of nitric oxide synthase (NOS) / NO signaling and upregulation of angiotensin II (Ang II) / Ang II receptor (AT1R) signaling in glomus cells. At the level of the CNS, interactions of the enhanced input from CB chemoreceptors with altered input from baroreceptor and cardiac afferent pathways and from central Ang II further enhance sympathetic drive. In addition, impaired function of NO in the paraventricular nucleus of the hypothalamus participates in the increased SNA response to CB chemoreceptor activation. These results underscore the principle that multiple mechanisms involving Ang II and NO at the level of both the CB and CNS represent complementary and perhaps redundant adaptive mechanisms to enhance CB chemoreflex function in CHF.
doi:10.1016/j.resp.2007.02.011
PMCID: PMC1965591  PMID: 17374517
20.  Mitochondria-Derived Superoxide Links to Tourniquet-Induced Apoptosis in Mouse Skeletal Muscle 
PLoS ONE  2012;7(8):e43410.
Our previous study has reported that superoxide mediates ischemia-reperfusion (IR)-induced necrosis in mouse skeletal muscle. However, it remains poorly understood whether IR induces apoptosis and what factors are involved in IR-induced apoptosis in skeletal muscle. Using a murine model of tourniquet-induced hindlimb IR, we investigated the relationship between mitochondrial dysfunction and apoptosis in skeletal muscle. Hindlimbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Compared to sham treatment, tourniquet-induced IR significantly elevated mitochondria-derived superoxide production, activated opening of mitochondrial permeability transition pore (mPTP), and caused apoptosis in the gastrocnemius muscles. Pretreatment with a superoxide dismutase mimetic (tempol, 50 mg/kg) or a mitochondrial antioxidant (co-enzyme Q10, 50 mg/kg) not only decreased mitochondria-derived superoxide production, but also inhibited mPTP opening and apoptosis in the IR gastrocnemius muscles. Additionally, an inhibitor of mPTP (cyclosporine A, 50 mg/kg) also inhibited both mPTP opening and apoptosis in the IR gastrocnemius muscles. These results suggest that mitochondria-derived superoxide overproduction triggers the mPTP opening and subsequently causes apoptosis in tourniquet-induced hindlimb IR.
doi:10.1371/journal.pone.0043410
PMCID: PMC3422247  PMID: 22912870

Results 1-20 (20)