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Simvastatin attenuates contractile dysfunction following ischemia and chronic reperfusion
HEART FUNCTION MODIFIES THE PATHWAYS OF DISCRIMINATION OF ENERGY TRANSFER : 31P NMR SUBCELLULAR CK FLUXES. Joubert F., Mateo, P., Mazet, J.-L. & Hoerter J.A., U-446 INSERM, Fat. Pharmacie, Universite Paris XI, Chatenay Malabry, France
SIMVASTATIN AlTENUATES CONTRACTILE DYSFUNCTlON FOLLOWING ISCHEMIA AND CHRONIC REPERFUSION Steven P. Jones and David J. Lefer. Dept. of Physiology, LSUHSC, Shreveport, USA The present study investigates the potential cardioprotective effects of simvaatatin treatment (1 mg/kg pretreatment) in mice subjected to 30 minutes of myocardial ischemia and 6 months of reperfusion. Myocardial necrosis was significantly reduced by 51% in the simvastatin group compared to the vehicle group. Using transthoracic echocardiography, we found that ventricular diastolic and systolic dilatation was attenuated (p&05) in simvastatin treated mice compared to vehicle. Insertion of a 1.4Fr Millar pressure transducer allowed for assessment of arterial and ventricular hemodynamic parameters. Although arterial hemodynamics were unaltered, left ventricular end diastolic pressure was significantly elevated (pcO.01) in vehicle (21+4 mmHg) but not simvastatintreated (52 mmHg) mice compared to baseline. These data demonstrate that simvastatin treatment prior to myocardial ischemia attenuates contractile dysfunction after chronic reperfusion in mice.
UPREGULATION OF AT, RECEPTOR AND CARDIOPROTECTION WITH VALSARTAN DOG AND RAT REPERFUSED INFARCTION Bodh I. Jugdott. University of Alberta, Edmontos
IN Alberta,
Canada
We have shown that cardiopmtection with angiotensin Il (AngII) type 1 (AT,) receptor blockade in dogs with myocxdial ischemiareperfusion is associated with type 2 (AT*) receptor activation. Whether ATI receptor blockade has a similar effect in rodents has not been de&mined. We measured the etkts of AT, receptor blockade with w&tan on in viva lefi ventricolar fimction (Echo/ Doppler) and infarct size (tehazoIium tetrachloride) and regional Angll type 2 (AT,) receptor expression (immunoblots) after tgerfmd anterior myocardial infarction in rats (60 min ischemia, 90 min reperkion, n = 28) and dogs (90 min ischemia, 120 mitt mperfnaiott, n= 17) randomized to pretmatm ent with valsartan (10 mg /kg i.v.) or vehicle control and sham groups. AT, receptor blockadewas confirmed by inhibition of AngU pressor responses.
*p
The investigation of the pathways of energy transfer and of the fluxes of subcellular creature kinases (CK) in the heart, by such a global method as NMR magnetization transfer, is a challenge because of the presence of intracellular compartmentation of enzymes and substrates. To discriminate the fluxes originating from CK bound isoforms (MM- and mito-CK), we developed in the control isovolumic pertirsed rat hearts a novel method analyzing simultaneously 4 different protocols of inversion transfer (inversion of PCr and y-ATP with and without Pi saturation, n=20). Through this strategy of increasing the analysis input information, several models of exchange involving 3-6 metabolite compartments were tested on quantitative criteria. In control heart the best model required to consider 3 different functioning of the CK : a cytosolic CK at equilibrium, a dominant synthesis of ATP for the bound MMCK and of PCr for the mito-CK, suggesting different substrates concentrations through the cell. Thus, at this working level, the energy is transferred by the PCr-Cr-CK shuttle. Upon partial inhibition of ATP synthesis by cyanide (n=20), mito-CK flux could not be detected. The energy left the mitochondria mainly by ATP diffusion. This strategy brings the first direct observation of the PCrCr-CK shuttle in the whole heart. Our results also suggest that the energy transfer pathways depend on the energetic status of the myocardium in physio-pathological situations. The same method can be applied to any kinetic data to assess the importance of compartmentation in the myocardium.
CHANGES IN OSTEOGLYCIN GENE EXPRESSION ARE LINKED TO ARTERIOGENESIS Andreas Kampmann, Borja Fernander’, Dietmar von der Ahe, Wolfgan Schaper” & Ren6 Zlmmermann. Vascular 8 enomlcs & ‘Max-Planck-Institute, Bad Nauhelm, Germany The molecular mechanism underlying arteriogenesis are only partial identified yet. In a search for #enes mvolved In thrs process Differential tsplay was performed with RNA isolated from tissue collected after 3 da s 7 days or 3 weeks of rabbit femoral artery occ Yuston and ‘. from normal arteries without occlusion as control. Differentially expressed mRNAs were cloned, sequenced, and their differential expression confirmed using Northern Hybridisation. Among others we identified a clone with homology to human osteoglycin (89%, Genbank Act. No. NM01 4057), a proteoglycan previously isolated as osteoinductive factor, that showed a marked downregulation (85% after 3d, p c 0.05). In situ hybridisation of a cDNA probe identified smooth muscle cells of arteries and collaterals as the main source of the RNA. The decrease in RNA at 3 days, stil obvious at 7 days and 3 weeks, was followed by a similar decrease in the glycosylated protein, shown by Western blot analysis and immunohistochemistry. This decrease in the protein was most prominent after 7 days of collateral artery growth. Our results point to an important role of osteoglycin in the growth of collateral arteries. A55
SIMVASTATIN AlTENUATES CONTRACTILE DYSFUNCTlON FOLLOWING ISCHEMIA AND CHRONIC REPERFUSION Steven P. Jones and David J. Lefer. Dept. of Physiology, LSUHSC, Shreveport, USA The present study investigates the potential cardioprotective effects of simvaatatin treatment (1 mg/kg pretreatment) in mice subjected to 30 minutes of myocardial ischemia and 6 months of reperfusion. Myocardial necrosis was significantly reduced by 51% in the simvastatin group compared to the vehicle group. Using transthoracic echocardiography, we found that ventricular diastolic and systolic dilatation was attenuated (p&05) in simvastatin treated mice compared to vehicle. Insertion of a 1.4Fr Millar pressure transducer allowed for assessment of arterial and ventricular hemodynamic parameters. Although arterial hemodynamics were unaltered, left ventricular end diastolic pressure was significantly elevated (pcO.01) in vehicle (21+4 mmHg) but not simvastatintreated (52 mmHg) mice compared to baseline. These data demonstrate that simvastatin treatment prior to myocardial ischemia attenuates contractile dysfunction after chronic reperfusion in mice.
UPREGULATION OF AT, RECEPTOR AND CARDIOPROTECTION WITH VALSARTAN DOG AND RAT REPERFUSED INFARCTION Bodh I. Jugdott. University of Alberta, Edmontos
IN Alberta,
Canada
We have shown that cardiopmtection with angiotensin Il (AngII) type 1 (AT,) receptor blockade in dogs with myocxdial ischemiareperfusion is associated with type 2 (AT*) receptor activation. Whether ATI receptor blockade has a similar effect in rodents has not been de&mined. We measured the etkts of AT, receptor blockade with w&tan on in viva lefi ventricolar fimction (Echo/ Doppler) and infarct size (tehazoIium tetrachloride) and regional Angll type 2 (AT,) receptor expression (immunoblots) after tgerfmd anterior myocardial infarction in rats (60 min ischemia, 90 min reperkion, n = 28) and dogs (90 min ischemia, 120 mitt mperfnaiott, n= 17) randomized to pretmatm ent with valsartan (10 mg /kg i.v.) or vehicle control and sham groups. AT, receptor blockadewas confirmed by inhibition of AngU pressor responses.
*p
The investigation of the pathways of energy transfer and of the fluxes of subcellular creature kinases (CK) in the heart, by such a global method as NMR magnetization transfer, is a challenge because of the presence of intracellular compartmentation of enzymes and substrates. To discriminate the fluxes originating from CK bound isoforms (MM- and mito-CK), we developed in the control isovolumic pertirsed rat hearts a novel method analyzing simultaneously 4 different protocols of inversion transfer (inversion of PCr and y-ATP with and without Pi saturation, n=20). Through this strategy of increasing the analysis input information, several models of exchange involving 3-6 metabolite compartments were tested on quantitative criteria. In control heart the best model required to consider 3 different functioning of the CK : a cytosolic CK at equilibrium, a dominant synthesis of ATP for the bound MMCK and of PCr for the mito-CK, suggesting different substrates concentrations through the cell. Thus, at this working level, the energy is transferred by the PCr-Cr-CK shuttle. Upon partial inhibition of ATP synthesis by cyanide (n=20), mito-CK flux could not be detected. The energy left the mitochondria mainly by ATP diffusion. This strategy brings the first direct observation of the PCrCr-CK shuttle in the whole heart. Our results also suggest that the energy transfer pathways depend on the energetic status of the myocardium in physio-pathological situations. The same method can be applied to any kinetic data to assess the importance of compartmentation in the myocardium.
CHANGES IN OSTEOGLYCIN GENE EXPRESSION ARE LINKED TO ARTERIOGENESIS Andreas Kampmann, Borja Fernander’, Dietmar von der Ahe, Wolfgan Schaper” & Ren6 Zlmmermann. Vascular 8 enomlcs & ‘Max-Planck-Institute, Bad Nauhelm, Germany The molecular mechanism underlying arteriogenesis are only partial identified yet. In a search for #enes mvolved In thrs process Differential tsplay was performed with RNA isolated from tissue collected after 3 da s 7 days or 3 weeks of rabbit femoral artery occ Yuston and ‘. from normal arteries without occlusion as control. Differentially expressed mRNAs were cloned, sequenced, and their differential expression confirmed using Northern Hybridisation. Among others we identified a clone with homology to human osteoglycin (89%, Genbank Act. No. NM01 4057), a proteoglycan previously isolated as osteoinductive factor, that showed a marked downregulation (85% after 3d, p c 0.05). In situ hybridisation of a cDNA probe identified smooth muscle cells of arteries and collaterals as the main source of the RNA. The decrease in RNA at 3 days, stil obvious at 7 days and 3 weeks, was followed by a similar decrease in the glycosylated protein, shown by Western blot analysis and immunohistochemistry. This decrease in the protein was most prominent after 7 days of collateral artery growth. Our results point to an important role of osteoglycin in the growth of collateral arteries. A55