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Isolated Hearts (isolated + heart)
Selected AbstractsImpaired Heart Function And Noradrenaline Release After Ischaemia In Stroke-Prone Spontaneously Hypertensive RatsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2000Hong Chen SUMMARY 1. Stroke-prone spontaneously hypertensive rats (SHRSP) are a strain of rat that exhibit severely high blood pressure and stroke attacks at an early age, but their heart function in vitro has seldom been studied in detail. Although the activity of the sympathetic nervous system is known to increase after myocardial ischaemia, there is little information about the cardiac release of noradrenaline (NA) associated with heart function after ischaemia in SHRSP. The aim of the present study was to examine heart function and cardiac NA release after ischaemia in SHRSP. 2. Isolated hearts of 4- and 8-month-old SHRSP and age-matched Wistar-Kyoto (WKY) rats were perfused in a working heart preparation and were subjected to 30 min ischaemia followed by 30 min reperfusion. Heart function and coronary flow were monitored throughout the experiment. Coronary effluent was collected for determination of NA using high- performance liquid chromatography coupled with electrochemical detection. 3. Under baseline conditions, cardiac output of 4-month-old SHRSP was slightly but significantly decreased compared with that of WKY rats (P < 0.05), although coronary flow was maintained normally at this age. Eight-month-old SHRSP showed a further impairment of systolic heart function, with lower coronary flow and higher coronary vascular resistance under baseline conditions. Elevated left ventricular end-diastolic pressure was evident in SHRSP at both ages before ischaemia. Heart function was severely damaged after 30 min global ischaemia in SHRSP from both age groups. Stroke-prone spontaneously hypertensive rats also showed lower coronary flow and higher coronary vascular resistance during reperfusion. 4. Coronary NA was not detectable in WKY rats or SHRSP at 4 months of age under baseline conditions. In 8-month-old SHRSP, pre-ischaemic NA release was significantly higher than that in age-matched WKY rat controls. The concentration of NA in the coronary effluent of SHRSP during reperfusion was also significantly higher than that of WKY rats at both ages. 5. These data demonstrate that SHRSP have early impairment of both systolic and diastolic heart function compared with WKY rats. Severe damage of heart function and coronary flow after ischaemia in SHRSP was accompanied with an increased release of NA, which may play a harmful role in heart function impairment in SHRSP after ischaemia. [source] Free radical generation and oxidative stress with ageing and exercise: Differential effects in the myocardium and liverACTA PHYSIOLOGICA, Issue 4 2000Bejma Reactive oxygen species and other oxidants are implicated in the mechanisms of biological ageing and exercise-induced tissue damage. The present study examined the effects of ageing and an acute bout of exercise on intracellular oxidant generation, lipid peroxidation, protein oxidation and glutathione (GSH) status in the heart and liver of young adult (8 month, N=24) and old (24 month, N=24) male Fischer 344 rats. Young rats ran on treadmill at 25 m min,1, 5% grade until exhaustion (55.4 ± 2.7 min), whereas old rats ran at 15 m min,1, 5% until exhaustion (58.0 ± 2.7 min). Rate of dichlorofluorescin (DCFH) oxidation, an indication of intracellular oxidant production, was significantly higher in the homogenates of aged heart and liver compared with their young counterparts. In the isolated heart and liver mitochondria, ageing increased oxidant production by 29 and 32% (P < 0.05), respectively. Acute exercise increased oxidant production in the aged heart but not in the liver. When nicodinamide dinucleotide phosphate (reduced), adenosine diphosphate and Fe3+ were included in the assay, DCFH oxidation rate was 47 and 34% higher (P < 0.05) in the aged heart and liver homogenates, respectively, than the young ones. The age differences in the induced state reached 83 and 140% (P < 0.01) in isolated heart and liver mitochondria, respectively. Lipid peroxidation was increased in the aged liver and exercised aged heart, whereas protein carbonyl content was elevated only in the aged heart (P < 0.05). Although our data using DCFH method probably underestimated cellular oxidant production because of time delay and antioxidant competition, it is clear that oxidative stress was enhanced in both heart and liver with old age. Furthermore, aged myocardium showed greater susceptibility to oxidative stress after heavy exercise. [source] Improved myocardial perfusion in chronic diabetic mice by the up-regulation of pLKB1 and AMPK signalingJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 5 2010Claudia Kusmic Abstract Previous studies related impaired myocardial microcirculation in diabetes to oxidative stress and endothelial dysfunction. Thus, this study was aimed to determine the effect of up-regulating pAMPK-pAKT signaling on coronary microvascular reactivity in the isolated heart of diabetic mice. We measured coronary resistance in wild-type and streptozotocin (STZ)-treated mice, during perfusion pressure changes. Glucose, insulin, and adiponectin levels in plasma and superoxide formation, NOx levels and heme oxygenase (HO) activity in myocardial tissue were determined. In addition, the expression of HO-1, 3-nitrotyrosine, pLKB1, pAMPK, pAKT, and peNOS proteins in control and diabetic hearts were measured. Coronary response to changes in perfusion pressure diverged from control in a time-dependent manner following STZ administration. The responses observed at 28 weeks of diabetes (the maximum time examined) were mimicked by L-NAME administration to control animals and were associated with a decrease in serum adiponectin and myocardial pLKB1, pAMPK, pAKT, and pGSK-3 expression. Cobalt protoporphyrin treatment to induce HO-1 expression reversed the microvascular reactivity seen in diabetes towards that of controls. Up-regulation of HO-1 was associated with an increase in adiponectin, pLKB1, pAKT, pAMPK, pGSK-3, and peNOS levels and a decrease in myocardial superoxide and 3-nitrotyrosine levels. In the present study we describe the time course of microvascular functional changes during the development of diabetes and the existence of a unique relationship between the levels of serum adiponectin, pLKB1, pAKT, and pAMPK activation in diabetic hearts. The restoration of microvascular function suggests a new therapeutic approach to even advanced cardiac microvascular derangement in diabetes. J. Cell. Biochem. 109: 1033,1044, 2010. © 2010 Wiley-Liss, Inc. [source] Mapping ischemic risk region and necrosis in the isolated heart using EPR imagingMAGNETIC RESONANCE IN MEDICINE, Issue 6 2003Murugesan Velayutham Abstract Reperfusion of ischemic tissue is a common event in the treatment of heart attack and stroke. To study disease pathogenesis, methods are required to measure tissue perfusion and area at risk, as well as localized regions of injury. While histology can provide this information, its destructive nature precludes assessment of time course. Thus, there is a critical need for a noninvasive technique to obtain this information. To map myocardial redox state as a possible index of cellular ischemia and viability, electron paramagnetic resonance (EPR) imaging experiments were performed on isolated rat hearts before and after the onset of regional ischemia using nitroxide spin labels. With coronary artery occlusion, the EPR images clearly showed the risk region as a void of lower intensity that reversed upon reperfusion. The extent of risk region in the heart was similar in EPR imaging and histological measurements. The unique information obtained regarding the time course of changes in redox metabolism of the risk region and normal myocardium can provide important insights regarding the mechanisms of myocardial injury during and following ischemia. Magn Reson Med 49:1181,1187, 2003. © 2003 Wiley-Liss, Inc. [source] New model for simultaneous heart and kidney transplantation in miceMICROSURGERY, Issue 2 2003Minghui Wang M.D. In clinical settings, combined heart and kidney transplantation results in a lower incidence of cardiac graft and renal graft rejection as compared to isolated heart and kidney transplantation. To study the phenomenon in an experimental setting, we developed a model of combined heart and kidney transplantation in mice. According to our technique, we kept the patch of the infrarenal aorta and inferior vena cava (IVC) as long as possible during the donor's kidney explantation, and then, after finishing the kidney implantation with conventional techniques, we anastomosed the innominate artery and pulmonary artery of the heart graft to the patch of the infrarenal aorta and IVC of the renal graft, respectively, instead of the recipient's aorta and IVC. With the use of our method, combined heart and kidney transplantation in mice can be performed to get enough suture room for the second graft, to avoid prolonging the occlusion time of the recipient's circulation, and to profoundly decrease postoperative complications such as paraplegia and mortality. Of the 14 recipients with combined heart-kidney isografting, 10 have been successful (71.4%), surviving over 100 days with normal function of both grafts, and with lack of change in histological appearance. This suggests that the technique is feasible and reliable. © 2003 Wiley-Liss, Inc. MICROSURGERY 23:164,168 2003 [source] Cardioprotective effect of sasanquasaponin preconditioning via bradykinin-NO pathway in isolated rat heartPHYTOTHERAPY RESEARCH, Issue 8 2009Zhangping Liao Abstract Sasanquasaponin (SQS) is an effective component of Camellia oleifera Abel. This study was designed to investigate the cardioprotective effect of SQS against ischemia-reperfusion (I/R) injury and the possible mechanism in isolated rat hearts. These hearts were pretreated by SQS only or SQS and HOE140 in different groups, and then subjected to I/R injury. Hemodynamic parameters, oxidative injury, and NO level were measured. The results showed that SQS preconditioning could decrease the incidences of arrhythmias and improve the heart functions. In addition, SQS preconditioning could protect isolated I/R injured heart against lipid peroxidation, as evidenced by increases in SOD and GSH-Px activity, and by decreases in contents of MDA, ROS generation. However, HOE140 treatment reversed all these indexes. NO production was significantly decreased after a treatment with HOE140. So we can propose that SQS preconditioning could induce the cardioprotective effects and the possible mechanism was that the activation of bradykinin-NO system by SQS preconditioning had an inhibition effect on ROS generation in isolated heart. Copyright © 2009 John Wiley & Sons, Ltd. [source] Ex vivo hypothermic recirculatory adenoviral gene transfer to the transplanted pig heartTHE JOURNAL OF GENE MEDICINE, Issue 7 2006Keiji Oi Abstract Background To facilitate the application of adenoviral gene therapy in clinical heart transplantation, we developed an ex vivo hypothermic recirculatory adenoviral gene transfer method to the transplanted pig heart. Methods Experimental animals were assigned into three groups; controls, 1 × 108 plaque-forming units (pfu)/ml group and 1 × 109 pfu/ml group. During the 30 min gene transfer perfusion, 200 ml of University of Wisconsin solution containing the adenoviral vector was recirculated through the coronary vessels. The myocardial temperature was maintained below 4 °C and the perfusion pressure was adjusted at 50 mmHg. Results Cardiac myocyte transduction efficiencies in the 1 × 108 pfu/ml group were 0.04% and 0.07%, whereas transduction efficiencies in the 1 × 109 pfu/ml group were widely distributed from 0.45% to 22.62%. The gene transduction efficiency increased with the virus titer. Additionally, no difference in the transduction efficiency was observed between different segments of the left ventricle. The current gene transfer method at 1 × 109 pfu/ml of adenovirus titer enabled homogeneous gene transduction into the transplanted pig heart up to a maximum of 22.62%. Conclusions This model can be applied to a large isolated heart and will greatly facilitate the investigation of gene therapy in large animal models of heart transplantation. Copyright © 2006 John Wiley & Sons, Ltd. [source] Carbon Monoxide Has Direct Toxicity on the Myocardium Distinct from Effects of Hypoxia in an Ex Vivo Rat Heart ModelACADEMIC EMERGENCY MEDICINE, Issue 1 2008Selim Suner MD Abstract Objectives:, Carbon monoxide (CO) toxicity causes significant central nervous system and cardiac injury. Although the neurological damage caused by CO toxicity is extensively described, the mechanisms underlying myocardial insult are unclear. The authors used an externally perfused isolated rat heart model to examine the effects of a physiological saline solution (Krebs Henseleit HEPES, KHH) aerated with CO on cardiac function. Methods:, Fifteen rats were equally divided into three groups: the control group (KHH + 100% O2), the nitrogen control group (KHH + 70% O2, 30% N2), and the CO group (KHH + 70% oxygen, 30% CO). Left ventricular peak systolic pressure (LVPsP), end diastolic pressure (LVEdP), and coronary perfusion pressure were measured while the isolated heart was paced and perfused on a modified Langendorf apparatus. Results:, Left ventricular generated pressure (LVGP = LVPsP , LVEdP) decreased in the nitrogen control and CO groups compared to the control group. There was higher LVGP in the recovery phase between the nitrogen control group compared to the CO group. Both groups had increased lactic acid levels in the experimental phase. Conclusions:, Carbon monoxide with hypoxia and hypoxemic hypoxia both result in similar depression of cardiac function. Hearts poisoned with CO with hypoxia do not recover function to the extent that hearts rendered hypoxic with nitrogen do when perfused with 100% oxygen after the insult. This suggests that CO causes direct myocardial toxicity distinct from the effects of hypoxia. [source] Exposure of rats to hyperoxia enhances relaxation of isolated aortic rings and reduces infarct size of isolated heartsACTA PHYSIOLOGICA, Issue 4 2002P. Tähepõld ABSTRACT Exposure of rats to hyperoxia before organ harvesting protected their isolated hearts against global ischaemia,reperfusion injury in a previous study. The present study investigates whether hyperoxia influences vasomotor function and regional ischaemia of the heart. Isolated rings of the thoracic aorta were obtained from rats immediately or 24 h after in vivo exposure to 60 min of hyperoxia (>95% O2), and the in vitro dose,response to phenylephrine (PHE), prostaglandin F2, (PGF2,) and endothelin-1 (ET-1), acetylcholine (Ach) and sodium nitroprusside (SNP) was assessed. Hyperoxia in vivo increased the relaxation of aortic rings to Ach and SNP, while it delayed contraction to PHE. The effect was more evident when the vessels were harvested immediately rather than 24 h after hyperoxic exposure. In separate experiments rat hearts were isolated immediately after hyperoxia, buffer-perfused, and subjected to 30 min of regional ischaemia and reperfused for 120 min. Infarct size was determined by triphenyl tetrazolium chloride staining. Hyperoxia significantly reduced infarct size. In normoxic controls 23.0 ± 8.3% of the area at risk was infarcted, while in hyperoxic animals infarct size was 14.8 ± 5.6% of the area at risk (P = 0.012). Exposure of rats to hyperoxia modifies the vasomotor response of isolated aortic rings, and reduces the infarct size of isolated rat heart. These novel aspects of hyperoxic treatment require further studies to explore the potential of its clinical application. [source] An abnormal gene expression of the ,-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats,HEPATOLOGY, Issue 6 2008Giulio Ceolotto Decreased cardiac contractility and ,-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study ,-adrenergic,stimulated contractility and ,-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10,10 to 10,6 M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha,inhibiting subunit 2 (G,i2), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of G,i2, PDE2a, and RGS2 down-regulates the ,-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy. (HEPATOLOGY 2008;48:1913-1923.) [source] Bacopa monniera protects rat heart against ischaemia,reperfusion injury: role of key apoptotic regulatory proteins and enzymesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2010Ipseeta Ray Mohanty Abstract Objectives, Rat isolated hearts were perfused in a Langendorff model to study the cardioprotective effects of Bacopa monniera, a medicinal herb used in the Indian system of medicine, on cardiomyocyte apoptosis and antioxidant status following ischaemia,reperfusion (I-R) injury. Methods, Forty-eight rats were randomly divided into four groups (12 in each group): sham group (no ischaemia,reperfusion injury), B. monniera control group (orally fed B. monniera at a dose of 75 mg/kg, for three weeks); ischaemia,reperfusion control group(subjected to ischaemia,reperfusion-induced myocardial injury) and B. monniera -treated group (same protocol as ischaemia,reperfusion control group except that rats also fed B. monniera). Key findings, Post-ischaemic reperfusion injury resulted in significant cardiac necrosis, apoptosis, depression of heart rate, decline in antioxidant status and elevation in lipid peroxidation. Oral administration of B. monniera per se for three weeks to healthy rats caused augmentation of myocardial antioxidants, superoxide dismutase, catalase and glutathione, along with induction of heat shock protein 72 (HSP72). Ischaemia,reperfusion-induced biochemical and histopathological perturbations were significantly prevented by B. monniera (75 mg/kg) pre-treatment. Interestingly, B. monniera also restored the antioxidant network of the myocardium and reduced myocardial apoptosis, caspase 3 and Bax protein expression. Conclusions, Histopathological studies and myocardial creatine phosphokinase content further confirmed the cardioprotective effects of B. monniera (75 mg/kg) in the experimental model of ischaemia,reperfusion injury. The study provides scientific basis for the putative therapeutic effect of B. monniera in ischaemic heart disease. [source] Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for IKsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010J Ducroq Introduction:, Doxorubicin, an anthracycline widely used in the treatment of a broad range of tumours, causes acute QT prolongation. Dexrazoxane has been shown to prevent the QT prolongation induced by another anthracycline, epirubicin, but has not yet been reported to prevent that induced by doxorubicin. Thus, the present study was designed to test whether the acute QT effects induced by doxorubicin could be blocked by dexrazoxane and to explore the mechanism. Results were compared with those obtained with a reference human ether-a-go-go (hERG) channel blocker, moxifloxacin. Methods:, The effects of moxifloxacin (100 µM) and doxorubicin (30 µM), with or without dexrazoxane (from 3 to 30 µM), have been evaluated on the QTc interval in guinea-pig isolated hearts and on IKr (rapid component of the delayed rectifier current) and IKs (slow component of the delayed rectifier current) currents stably expressed in human embryonic kidney 293 cells. Results:, Moxifloxacin (100 µM), a potent hERG blocker, prolonged QTc by 22%, and this effect was not prevented by dexrazoxane. Doxorubicin (30 µM) also prolonged QTc by 13%, did not significantly block hERG channels and specifically inhibited IKs (IC50: 4.78 µM). Dexrazoxane significantly reduced the doxorubicin-induced QTc prolongation and prevented doxorubicin-induced inhibition of IKs. Conclusion and implications:, Doxorubicin acutely prolonged the QT interval in guinea-pig heart by selective IKs blockade. This effect was prevented by dexrazoxane. This result is important because it illustrates the danger of neglecting IKs in favour of hERG screening alone, for early preclinical testing for possible induction of torsade de pointes. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 [source] Roles of KATP channels in delayed cardioprotection and intracellular Ca2+ in the rat heart as revealed by , -opioid receptor stimulation with U50,488HBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Mai Chen The effect of preconditioning with U50,488 H (UP), a selective kappa-opioid receptor (, -OR) agonist, on infarct size and intracellular Ca2+ ([Ca2+]i) in the heart subjected to ischaemic insults were studied and evaluated. U50,488 H administered intravenously reduced the infarct size 18,48 h after administration in isolated hearts subjected to regional ischaemia/reperfusion (I/R). The effect was dose dependent. A peak effect was reached at 10 mg kg,1 U50,488 H and at 24 h after administration. The effect of 10 mg kg,1 U50,488 H at 24 h after administration was abolished by nor-binaltorphimine (nor-BNI), a selective , -OR antagonist, indicating the effect was , -OR mediated. The infarct reducing effect of U50,488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (KATP) was coadministered with U50,488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. U50,488 H also attenuated the elevation in [Ca2+]i and reduction in electrically induced [Ca2+]i transient in cardiomyocytes subjected to ischaemic insults. The effects were reversed by blockade of KATP channel, which abolished the protective effect of preconditioning with U50,488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of , -OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults. British Journal of Pharmacology (2003) 140, 750,758. doi:10.1038/sj.bjp.0705475 [source] INVESTIGATION OF THE MICROCIRCULATION AND THE STATE OF OXIDATIVE STRESS IN THE RAT AFTER SCORPION ENVENOMATIONCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2007Z Sahnoun SUMMARY 1Severe cases of scorpion envenomation (SE) generally show both respiratory and cardiocirculatory dysfunction. However, the pathophysiology of SE remains controversial. In the present study, we tried to explain the pathophysiology of the haemodynamic perturbations and cardiac failure in rats poisoned by the venom of Buthus occitanus tunetanus through a histomorphometric study of myocardial and muscular skeletal microcirculation and analysis of the oxidative stress state in order to evaluate the implication of the inflammatory process in the pathogenesis of SE. 2Experiments were performed on 96 rats divided into 16 groups (n = 6 in each group). Two groups were used to determine the optimum conditions of venom administration and times when to measure haemodynamic parameters. The B. occitanus tunetanus venom was administered at a dose of 800 µg/kg and tissues were removed 5 and 20 min after envenomation. Six groups were used for histomorphometric study: two control groups, two poisoned groups an two melatonin-pretreated and poisoned groups. The histomorphometric study was performed on isolated hearts and skeletal muscles. The final eight groups of rats (two control groups, two envenomated groups, two control groups pretreated with melatonin and two groups pretreated and envenomated) were used to investigate the state of tissue oxidative stress during SE and to evaluate the anti-oxidant effect of melatonin on rats poisoned with B. occitanus tunetanus venom. This study was based on the determination of tissue malondialdehyde in isolated organs as an indicator of thiobarbituric acid-reactive substances (TBARS). Melatonin was injected at a dose of 5 mg/kg, i.v., 15 min before the administration of serum or venom. Data were compared using analysis of variance and Tukey's test for multiple pair-wise comparisons. 3Five minutes after venom injection, a significant reduction in the mean relative volume of venules and arterioles in the heart and skeletal muscles of poisoned rats was noted. Twenty minutes after venom injection, these volumes were significantly increased in the heart and skeletal muscles of poisoned rats. Pretreatment of envenomated rats with melatonin resulted in a significant decrease in the mean relative volume of the venules and arterioles in the heart and skeletal muscles 5 and 20 min after venom injection compared with untreated envenomated rats. Investigation of the oxidative stress state showed a highly significant increase in TBARS in poisoned rats compared with control groups 5 and 20 min after venom injection. Melatonin pretreatment of rats poisoned with B. occitanus tunetanus venom resulted in an important and highly significant reduction of TBARS compared with untreated envenomated rats. 4It appears from the results of the present study that administration of B. occitanus tunetanus venom engendered an excessive myocardial and skeletal muscular vasoconstriction attributed to massive catecholamine release followed by arteriolar and venular vasodilatation. This venous stasis at the muscular microcirculation could be due to myocardiac failure. However, the concomitant presence of arteriolar vasodilatation suggests an inflammatory process in the pathophysiology of SE. This process was suggested by the genesis of a state of oxidative stress in relation to the important lipoperoxidation, which was inhibited by administration of the anti-oxidant melatonin. Thus, melatonin pretreatment seemed to accentuate the first phase of vascular reactivity in envenomed rats and inhibit the second vasodilator phase observed 20 min after administration of the venom. [source] In vivo Remote Delivery of DNA Encoding for Hypoxia-inducible Factor 1 Alpha Reduces Myocardial Infarct SizeCLINICAL AND TRANSLATIONAL SCIENCE, Issue 1 2009Gabor Czibik M.D. Abstract We tested if remote gene delivery of hypoxia-inducible factor 1 alpha (HIF-1,) protected hearts against induced ischemia, hypothesizing that gene delivery into skeletal muscle may lead to secretion of proteins with actions elsewhere. Murine quadriceps muscles were transfected with DNA encoding for human HIF-1,, which resulted in a local, but lasting expression (mRNA and protein, where the latter had nuclear localization). Subjection of isolated hearts to global ischemia and reperfusion 1, 4, and 8 weeks after gene delivery resulted in infarct size reduction (p < 0.05). Supporting that this was due to paracrine effects, HL-1 cells treated with conditioned media from cells transfected with HIF-1, or serum from HIF-1,-treated mice were protected against H2O2 -induced cell death (p < 0.05, respectively). The latter protection was reduced when a heme oxygenase activity blocker was used. Taqman low-density array of 47 HIF-1,-regulated genes at the treatment site showed nine specific upregulations (p < 0.05). Of the corresponding proteins, PDGF-B and adrenomedullin were upregulated in the heart. HIF-1, treatment induced an increased vascularization of the heart and skeletal muscle. In conclusion, remote delivery of DNAfor HIF-1, was cardioprotective, represented by consistent infarct size reduction, which may be due to release of paracrine factors from the transfected muscle. [source] | |||||||||||||