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The effect of apolipoprotein B polymorphisms on the lipid-regulating therapy for hyperlipidemia
THE ROLE OF THE MITCCHONDRIAL ATPASE INHIBITOR, IFI. IN CARDIAC ATP CONSERVATION UNDER HYPOXICASCHEMIC CONDITIONS Fouad Y. Shataby, Wayne A. Little, Salkrushna C. Panchal, Brian L. Patton, Feng-Lai Wang, Lindsey 6. Ciali, Patricia A. Ferrer, Kara 6. Anthony, David W. Green, Nick C. Trippodo, Cart S. Madsen, and Michael A. Planar. Cardiovascular and Metabolic Diseases Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute. Princeton NJ OS543-4tlOCr. Previous pharmacological studies have shown that a significant loss of ATP can be attributed to the hydrolase activity of the mitochondrtal Fl FO ATP synthase in the ischemic heart. The ATPase inhibitor, IFl, is a small protein, that inhibits the hydrolase activity without affecting the synthase activity of the enzyme. Thus, it has been hypothesized that it functions to conserve ATP under ischemtiypoxic conditions. We cloned full-length cDNAs encoding the human and the mouse proteins and found that over-expression of human IF1 in HEKZ93 cells leads to a significant increase in ATP conservation upon uncoupling of oxidative phosphorylatton. We show that IF1 mRNA is expressed ubiquitously at low levels in both humans and mice. However, higher levels are found in the heart. We generated transgenic mice expressing high levels of human IF1 under transcriptional control of the cardiac-specific promoter of the a-myosin heavy chain gene. The ATP hydrolase activity in the heart mitochondrial fraction of these mice is 10 fold lower than in controls, while the synthase activity is not affected. Global ischemia-induced contracture of hearts isolated from these mice is delayed significantly, relative to non-transgenic controls, indicating a decreased rate of ATP depletion. These results suggest a role for IF1 in ATP presewation under ischemic conditions.
The effect of selenium on plasma lipoprotein levels and lipoproteialipsse activity in hype rthyroidism An Antirtheragenic action.
i?iitym. Sha&t Mohsen. Ani Isfahan Cardiovascular kesearch Center, Isfahan, Iran The involvement of selemmn in biochemical changes 1s known for a long time. It has been made clear that there are some s&no enzymes thatplay very important roles in normal cell metabolism and also in antioxidation reactions. A wellknown s&no enzyme is thyroxin-5’deicnlinase which catalysis the conversion of thy~oxin(T4) to tri-iodothyronin (T3). Thus there is a close relationship between selenium and normal thyroid function. On the other hand change in the serum levels of different lipid fractions in hype-and hyperthyroidism is well stablished. In this study the effect of selenium on serum lmid fractions is studied. Methods: Wistar rats (250-300 gr) were made hype-and/or hyperthyoids using metimazole or levo-thyroxine. Different doses of selenium were then injected to animals for 40 days. Rats were then killed. their bloods were collected and analvsed for different lipid f&ions, and compared with control an&Is. Results: Preliminary expaiments revealed that the umcentrations of cholesterole and LDL increased significantly in hypothyroid animals, the increase in triglyceride and HDL levels were not Very significant. Results showed that selenium treatment could reverse the change occurred in the levels of lipoproteins. Lipid parameters, on the other hand, were decreased in hyperthvroidism, except for HDL, but reached the control levels &er Gatement of th; animals with selenium Conclusions: It is concluded that selenium could affect lipoprotein metabolism in hype-and hyperthyroidim. More investigation is needed to clear@ the mechanism of this effect. Objective:
TIN!
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APOl.IPOPNOl-EIN
POLYMORPHISMS ON THE UPID-REOULATINQ THERAPY FOR HYPERLlPIDEMlA shmmg Yan-ahong, Y. Ping. Dapt of cerdfflog~ Qonml Horpltal, MlJlnp, chin=
6
PIA
Objective: To study the efficacy of simvastatin in treatment of hyperlipidemia with small dosage, and to investigate the effect of polymorphisms in apoB gene on the efficacy of the treatment to hyperlipidemia. Methods: S&y-one patients with hypedipidemia were selected and simvastatin SmgNl was used. TC, TG, HDL, LDL. &JAI and ApoB and the function of liver and kidney wsra measured on every patient at pretmabnent and 4, 8, 12 weeks arter treated. RFLPs was applied for determination for polymorphisms on Xbal locus of the apo.6 gene. Result: In the total of 61 patients, X+Xgenotype in 5 patients (8.20%), and X-X- ganotype was found in 56 patients (91.80%), no X+X+ genotype was found. The relative frequency of X+ allele was 0.041. and X- allele was 0.959, suggesting X- allele still a dominant one in the parents with hypedipidemia. The result was showed that small dosage of simvastatin could effectiveiy reduce blood levels of TC, TG, LDL-C and ApoB. The levels of TC and LDL-C lowering was more prominent in X-Xqenotypa than that in X+X- genotype (27.62% and 35.02% vs. 22.36% and 20.05%, PcO.05). While HDL-C and ApoAl increasing was mom obvious in X+X- genotype compared with X-Xgenotype (3.67% and 39.25% vs. 2.26% and 6.83%. fQO.05). Conclurlon: The relative fraquancy of X+ allele was higher in patients with hyperlipidemia when compared to normal peoples. The effect on treated by lipid-lowering was ineffactive with the patients who have this allele.
DEPRESSED CONTRACTILE FUNCTION OF RAT ISOLATED CARDIOMYOCYTES DURING SEPSIS Avadhesh C. Sharma’, Bonnie H. Ren* 8 Jun Ren*. ‘Dept. of Phann. Sci., College of Pharmacy, North Dakota State Univ., Fargo, ND., *Dept of Pharmacol., Physiol. & Therapeut., Univ. of North Dakota School of Medicine 8 Health Sciences, Grand Forks, ND. The present study was designed to test the hypothesis that induction of sepsis would produce dysfunction in the mechanical properties and intracellular Ca** handling of cardiomyDcytes isolated from rats. Mechanical properties were evaluated by use of a video edge-detection system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-go% relengthening (TR,), and maximal velocities of shortening and relengthening (*dUdf). Intracellular Ca2+ handling was evaluated with fura- fluorescent dye. Myocytes from 24 hr- septic animals exhibited a depressed PS (85% of control), normal TPS, prolonged T$, (147% of control), and reduced &dL/dt (both 79% of control). Myocytes from 48 hr-septic animals also exhibited a reduced peak of intracellular Ca*’ sequestration (55% of control). However resting intracellular Ca” and Ca*‘-transient decay were comparable to the values seen in myocytes from untreated rats. Cardiomyocytes from septic animals were unresponsive (5% of control) to increase of excellular Ca*+ (0.5- 3 mM). The data demonstrate that there are substantial deficits in cardiac function during peritoneal sepsis in the rat.
A109
The effect of selenium on plasma lipoprotein levels and lipoproteialipsse activity in hype rthyroidism An Antirtheragenic action.
i?iitym. Sha&t Mohsen. Ani Isfahan Cardiovascular kesearch Center, Isfahan, Iran The involvement of selemmn in biochemical changes 1s known for a long time. It has been made clear that there are some s&no enzymes thatplay very important roles in normal cell metabolism and also in antioxidation reactions. A wellknown s&no enzyme is thyroxin-5’deicnlinase which catalysis the conversion of thy~oxin(T4) to tri-iodothyronin (T3). Thus there is a close relationship between selenium and normal thyroid function. On the other hand change in the serum levels of different lipid fractions in hype-and hyperthyroidism is well stablished. In this study the effect of selenium on serum lmid fractions is studied. Methods: Wistar rats (250-300 gr) were made hype-and/or hyperthyoids using metimazole or levo-thyroxine. Different doses of selenium were then injected to animals for 40 days. Rats were then killed. their bloods were collected and analvsed for different lipid f&ions, and compared with control an&Is. Results: Preliminary expaiments revealed that the umcentrations of cholesterole and LDL increased significantly in hypothyroid animals, the increase in triglyceride and HDL levels were not Very significant. Results showed that selenium treatment could reverse the change occurred in the levels of lipoproteins. Lipid parameters, on the other hand, were decreased in hyperthvroidism, except for HDL, but reached the control levels &er Gatement of th; animals with selenium Conclusions: It is concluded that selenium could affect lipoprotein metabolism in hype-and hyperthyroidim. More investigation is needed to clear@ the mechanism of this effect. Objective:
TIN!
eFPEM
Of
APOl.IPOPNOl-EIN
POLYMORPHISMS ON THE UPID-REOULATINQ THERAPY FOR HYPERLlPIDEMlA shmmg Yan-ahong, Y. Ping. Dapt of cerdfflog~ Qonml Horpltal, MlJlnp, chin=
6
PIA
Objective: To study the efficacy of simvastatin in treatment of hyperlipidemia with small dosage, and to investigate the effect of polymorphisms in apoB gene on the efficacy of the treatment to hyperlipidemia. Methods: S&y-one patients with hypedipidemia were selected and simvastatin SmgNl was used. TC, TG, HDL, LDL. &JAI and ApoB and the function of liver and kidney wsra measured on every patient at pretmabnent and 4, 8, 12 weeks arter treated. RFLPs was applied for determination for polymorphisms on Xbal locus of the apo.6 gene. Result: In the total of 61 patients, X+Xgenotype in 5 patients (8.20%), and X-X- ganotype was found in 56 patients (91.80%), no X+X+ genotype was found. The relative frequency of X+ allele was 0.041. and X- allele was 0.959, suggesting X- allele still a dominant one in the parents with hypedipidemia. The result was showed that small dosage of simvastatin could effectiveiy reduce blood levels of TC, TG, LDL-C and ApoB. The levels of TC and LDL-C lowering was more prominent in X-Xqenotypa than that in X+X- genotype (27.62% and 35.02% vs. 22.36% and 20.05%, PcO.05). While HDL-C and ApoAl increasing was mom obvious in X+X- genotype compared with X-Xgenotype (3.67% and 39.25% vs. 2.26% and 6.83%. fQO.05). Conclurlon: The relative fraquancy of X+ allele was higher in patients with hyperlipidemia when compared to normal peoples. The effect on treated by lipid-lowering was ineffactive with the patients who have this allele.
DEPRESSED CONTRACTILE FUNCTION OF RAT ISOLATED CARDIOMYOCYTES DURING SEPSIS Avadhesh C. Sharma’, Bonnie H. Ren* 8 Jun Ren*. ‘Dept. of Phann. Sci., College of Pharmacy, North Dakota State Univ., Fargo, ND., *Dept of Pharmacol., Physiol. & Therapeut., Univ. of North Dakota School of Medicine 8 Health Sciences, Grand Forks, ND. The present study was designed to test the hypothesis that induction of sepsis would produce dysfunction in the mechanical properties and intracellular Ca** handling of cardiomyDcytes isolated from rats. Mechanical properties were evaluated by use of a video edge-detection system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analyzed included peak shortening (PS), time-to-peak shortening (TPS), time-to-go% relengthening (TR,), and maximal velocities of shortening and relengthening (*dUdf). Intracellular Ca2+ handling was evaluated with fura- fluorescent dye. Myocytes from 24 hr- septic animals exhibited a depressed PS (85% of control), normal TPS, prolonged T$, (147% of control), and reduced &dL/dt (both 79% of control). Myocytes from 48 hr-septic animals also exhibited a reduced peak of intracellular Ca*’ sequestration (55% of control). However resting intracellular Ca” and Ca*‘-transient decay were comparable to the values seen in myocytes from untreated rats. Cardiomyocytes from septic animals were unresponsive (5% of control) to increase of excellular Ca*+ (0.5- 3 mM). The data demonstrate that there are substantial deficits in cardiac function during peritoneal sepsis in the rat.
A109