Stanford BIOC 230 - Molecular Interventions for Cardiovascular Disease - It Isn't That Simple!

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Molecular Interventions for Cardiovascular Disease:It Isn't That Simple!A Cautionary TaleCauses of death, 2001:1. Infectious and parasitic diseases: 14.9 million2. Heart diseases: 11.1 million3. Cancers: 7.3 million4. Stroke: 5.5 million5. Respiratory diseases: 3.6 million6. Accidents, fires, drowning, etc.: 3.5 million7. Maternal and perinatal: 3.0 million8. Violence (war, homicide, suicide): 1.6 million World Health OrganizationWorld Health Report 2002Population: 6,122,210,000Deaths: 56,554,000USA6.1.2.3.4.5.AtherosclerosisRisk increases with higher [LDL]Risk decreases with higher [HDL]Familial Hypercholesterolemia (FH)XanthomaHeterozygotes (1:500) 300-500 mg/dl plasma cholesterol Xanthomas in third decade Coronary heart disease in fourth decade Treat w/ statins and bile acid binding resinsHomozygotes (1:10^6) 500-1200 mg/dl plasma cholesterol Xanthomas at birth Death by MI before age 30 Treat w/ plasma LDL apheresisCholesterol1) Acetyl-CoA → HMG-CoA → Mevalonate2) Mevalonate (C6) + 3ATP → Isopentenyl-PPi (C5 “isoprene”) + CO2 + 3ADP + Pi3) 6 Isoprene units (C5) → Squalene (C30)4) Squalene (C30) → Cholesterol (C27)Isopentylpyrophosphate (MEV Pathway)The StatinsSHORT HISTORY• 1976 Mevastatin fromPenicillinum citrinum•1980 Mevinolin fromAspergillus terreus•1987 FDA approvesLovastatin•1988 Lovastatin not effectivein FH homozygotes•1995 Pravastatin decreasesheart transplant rejection andmortality independently oflowering cholesterol levelsSTATINS REDUCE [CIRCULATING CHOLESTEROL] BY UP TO 50%FAIRLY SAFE (rhabdomyolysis)Lipid Trafficking EnzymesAlso CETPLipoprotein ParticlesCMC, VLDL, IDL, HDL; bindsreceptor0.03-0.0538 kDApoEHDL0.06-0.0733 kDApoDCMC, VLDL, HDL0.12-0.149 kDApoC-IIICMC, VLDL, HDL; activates LPL0.03-0.059 kDApoC-IICMC, VLDL, HDL0.04-0.067 kDApoC-IVLDL, IDL, LDL; binds receptor0.7-1.0512 kDApoB-100CMC; (intestine only)0.03-0.05264 kDApoB-48CMC, HDL0.15-0.1646 kDApoA-IVCMC, HDL0.3-0.517 kDApoA-IICMC, HDL; activates LCAT1.0-1.228 kDApoA-ICommentsgL-1M.W.ApolipoproteinApoA-I Milano Clinical Trial in Humans, JAMA 290(17):2292 2003ApoB RNAi in Mice, Nature 432:173 2004Lipoprotein TransportIDEA:Statins act by inhibiting cholesterol synthesisin patients.Clinical ObservationUauy et al. Journal of Pediatrics 113(2): 7387-92 (1988).Sterol Regulation of Transcription by SREBPSREPB Transcription Factor LocalizationER Retention ProteasesE.R.E.R. Golgi.Golgi.NucleusSCAP/Insig proteinsalso (HMG CoA R)S1P S2PSSDIDEA:Statins act by activating SREBP, resulting inincreased LDL receptor and more efficientrecruitment of LDL out of plasma.Clinical Observations:The Pleiotrophic Effects of StatinsKobashigawa et al. N. Eng. J. Med. 333(10): 621-627 (1995).• Statins reduce organ rejection and mortality aftercardiac transplant. Randomized, placebo-controlled• Statins reduce inflammation in patients withchronic rheumatoid arthritis. Randomized, placebo-controlledMcCarey et al. Lancet 363: 2015 (2004).• Statins reduce incidence of MS lesions. Smallopen-label clinical trial.Vollmer et al. Lancet 363: 1607 (2004).• Statins reduce proteinuria in sytemic lupuserythematosus. Small open-label clinical trial.Abud-Mondoza et al. Lupus 12: 607 (2003).Multiple Sclerosis• Effects up to one million worldwide• 16,000 deaths in 2002 (0.03 %)• Autoimmune attack of myelin in brain and spinalcord• Progressive physical disability• Current therapies include injected Ifn-β andcopaxone (basic peptides)Lesions on cerebellum and spinal cord ofan MS patient; Jean Cruvelhier circa 1860• Statins reverse disease pathology in the EAE mousemodel of MS!Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M,Mitchell DJ, Sobel RA, Steinman L, Zamvil SS. “The HMG-CoA reductaseinhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis incentral nervous system autoimmune disease.” Nature 420: 78-84(2002).Immune System OverviewInate AdaptiveNK cellsAPC B cells T cellsprofessionalIfn-γinducedγδCD4helperCD8cytotoxicTH1 TH2IL2Ifn-γTNFαIL4, 10TGFβIfn-βIL12 from activatedmacrophages anddendritic cells+Cell Mediated Adaptive Immune ResponseTc/MHC1/CD8 versus Th/MHC2/CD4MHC Antigen PresentationExpressed in ALLCELLSExpressed inPROFESSIONAL APCINF-γ can induceexpression in non-APCduring acute immuneresponse; this is also ahallmark of auto-immunediseasesThe MHC MoleculesClass I Class IIDifferent Responses to Different PathogensTh1 vs. Th2 Helper Cellsextracellular pathogense.g. helminthsalso oral antigensLFA-1 !Th1 Helper Cells (macrophage/inflammatory)Th2 Helper Cells (B cell response)also mast cell degranulation andeosinophil activationhigh [antigen], nonprofessionalTh1 vs. Th2 AntagonismSTATINS ALTER THIS BALANCE IN FAVOR OF TH2 HELPER CELLS.BUT HOW?Statins Bind to LFA-1 DirectlyIsoprenoids in Humans1. Steroids Hormones2. Metabolites (Vit. A, E, K; co-Q; 25,000 terpenoids)3. Isopentyl adenosine (tRNA)4. Dolichol (N-linked glycosylation)5. Protein PrenylationIsoprenoids in G Protein SignalingHeterotrimeric (GPCR’s)“Small” (RTK’s)How Do Statins Work?Reported to:• Decrease occurrence of AD by 70% in retrospective study• Suppress MS (clinical trials)• Block SMC proliferation/migration in vitro• Modulate NF-κB Function in vitro• Block IFN-γ induced MHCII expression in vitro• Suppress expression/secretion of immunoinflammatory molecules in vitro• Direct inhibition of LFA-1Most in vitro effects reversed by mevalonate, transF, transGG, but not cisF, cisGG,squalene, isopentyl adenosine or ubiquinone; prenylation inhibitors have many ofthe same immunomodulatory effects that are observed for statins.The Next Cardiovascular Blockbuster?: Torcetrapib• Rationally designed inhibitor of CETP.• Reduces in vivo [LDL]/[HDL] < 1!• Decreases atherogenesis in the rabbit model.• Additive effects w.r.t. statins.The Next Cardiovascular Blockbuster?: Ezetimibe• Cholesterol absorption inhibitor derived from ACAT inhibitors.• Discovered using in vivo hypocholesterolemic hamster assay!• The target was unknown during the discovery process.• Reduces cholesterol absorption by 75% in mice.• Reduces plasma cholesterol by 20% in humans.• Additive effects w.r.t. statins.How do Torcetrapib and Ezetimibe work?Kastelstein et al. “Effect of Torcetrapib on Carotid Athersclerosis in Familial Hypercholsterolemia.” NewEngl. J. Med. 356(16): 1620-30 (2007).Garcia-Calvo


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Stanford BIOC 230 - Molecular Interventions for Cardiovascular Disease - It Isn't That Simple!

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