Block 3 - Cardiac

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  1. Humoral vasodilators:
    • -epinephrine
    • -vasoactive intestinal peptide (VIP)
    • -atrial natriuretic peptide (ANP)
  2. Humoral vasoconstrictors
    • -renin-angiotensin system
    • -vasopressin (ADH)
    • -norepinephrine (negligible)
  3. Norepinephrine:
    • -released from sympathetic nerve terminals
    • -activates alpha-adrenergic receptors
    • -vasoconstriction of both arterioles and veins
  4. Epinephrine:
    • -released from adrenal glad
    • -activates Beta1 (heart) and Beta2 (lungs) and also alpha-adrenergic receptors
    • -stimulation of beta receptors much greater than alpha
    • -vasodilation
  5. Intrinsic regulation of blood flow:
    • Myogenic response:
    • -increase in arterial pressure, causes an increase in vascular smooth muscle cell contraction => no pressure change in capillaries and constant blood flow
    • -endothelial independent
  6. Endothelial dependent regulation of blood flow:
    • -Prostacyclin (PGI)
    • ↑ shear stress=>↑PGI=>↑cAMP=>relaxation
    • -nitric oxide 
    • ↑ATP,Ach, bradykinin,serotonin,histamine,shear stress=>conversion of L-arginine into NO=>↑cGMP=>↓ myofilament sensitivity to Ca2+=>relaxation
    • -nitroprusside 
    • ↑cGMP independent of endothelium
    • -parenchymal tissue
    • Adenosine,H+,CO2,K+ =>relaxation
    • -endothelin - potent vasoconstrictor
  7. Cholera
    • -caused by vibrio cholerae
    • -cholera toxin=>modification of G-alpha stimulatory subunit=>remains active
    • -↑cAMP=>↑PKA activity=>↑CFTR activity=>H2O and Cl- loss from intestinal epithelial cells
  8. Whooping Cough
    • -caused by bordatella pertussis
    • -pertussis toxin=>modification of G-alpha inhibatory subunit=>prevents GDP release=>inhibatory signal inactivated
    • -↑cAMP=>↑PKA activity=>↑fluid loss from lung epithelia
  9. Smooth Muscle Relaxation
    Ach=>GPCR=>PLC=>IP3=>Ca2+/Calmodulin=>NO synthase=>NO=>NO receptor=>cGMP=>PKG=>muscle relaxation
  10. Single pass membrane receptors
    • -cytokine receptors (extrinsic kinases) (JAK/STAT)
    • -receptor tyrosine kinases (intrinsic kinases)
    • (Ras+SOS=>Raf=>MEK=>ERK(MAPK)
    • -TGFbeta receptors (intrinsic kinases)
  11. Examples of cytokine receptors
    • -interferon response
    • -prolactin signaling=>mammary gland milk production
    • -hematopoetic RBC production
  12. Examples of receptor tyrosine kinases
    • -epidermal growth factor receptor (EGFR)
    •           -deregulated in cancer
    • -vascular endothelial growth factor receptor (VEGFR)
    •            -angiogenesis
    • -insulin receptor (glucagon receptor is GPCR)
    •            -inactivated in some types of diabetes
  13. Examples of TGFbeta receptors
    • -secretion of extra cellular matrix proteins, and PAI1 (plasminogen activator inhibitor 1)
    • -PAI1 inhibits matriz proteases, preventing cancer metastasis
    • -TGFbeta signaling has anti-growth properties=>induces CDK1 p15 and PAI1
  14. Omega 3 and 6 fatty acids:
    • - α-Linolenic acid (ALA, 18:3, ω-3), must be supplied in diet
    • - Eicosapentaenoic acid (EPA, 20:5, ω-3)
    • - Docosahexaenoic acid (DHA, 22:6, ω-3)
    • - Linoleic acid (18:2, ω−6), must be supplied in diet
    • - Arachidonic acid (ARA, 20:4, ω−6), a prostaglandin/leukotriene precursor
  15. Saturated fatty acids:
    • -Lauric acid C12
    • -Myristic acid C14
    • -Palmitic acid C16
    • -Stearic acid C18
  16. Partial Hydrogenation:
    • -↓ cis bonds, ↑ trans bonds
    • -↑ melting temp, ↑ shelf life
  17. Triacylglyceride functions:
    • -energy storage
    • -protects organs
    • -thermal insulation (brown fat)
    • -carrier and transport for fat soluble proteins
  18. Steatorrhea
    • -caused by absorption problems (shortened bowls) or digestion problems (CF causes thickening of intestinal secretions)
    • -treatment with short and medium chain f.a.
  19. Mobilization of TG:
    • 1) Glucagon/Epinephrine GPCR signaling activate cAMP-dependent PKA
    • 2) PKA phosphorylates Hormone sensitive lipase and Perilipin
    • 3) Hormone sensitive lipase phosphorylates Perilipin, allowing it to access fat droplet Fas
    • 4) Lipase hydrolyzes TGs into glycerol and fFAs
    • 5) fFAs bind to albumin in blood and are transported to peripheral cells for fuel
  20. B-oxidation steps:
    • 1) Oxidation by acyl-CoA dehydrogenase
    • 2) Hydration by enoyl-CoA hydratase
    • 3) Oxidation by Beta-hydroxyacyl-CoA dehydrogenase
    • 4) Cleavage by acyl-CoA acetyltransferase
  21. B-oxidation products after each round:
    • -remove 2C unit
    • -Acetyl-CoA
    • -FADH2
    • -NADH
    • -after 7 rounds, 7 FADH2/NADH, but 8 acetyl-CoA =>108ATP
  22. Medium Chain Acyl-CoA Dehydrogenase deficiency (MCADD):
    • -autosomal recessive
    • -reduced ability to oxidize f.a of 6-10C in length=>build-up in liver, hypoglycemia, high blood octanoic acid levels
    • -diagnosed by high 6-10C mono and dicarboxylic acids in urine b/c since B-oxidation not working, alternative pathway used, producing the mono and dicarboxylic acids
  23. Oxidation of odd chain length f.a.
    • -Carboxylation of Proprionyl CoA yields Methylmalonyl CoA, which is converted to Succinyl CoA in Biotin and vitamin B12 dependent rxns
    • -methylmalonyl CoA mutase deficiency=>build-up of propionyl CoA
  24. Refsum Disease
    • -genetic defect in phytanoyl-CoA hydroxylase (the first enzyme in the alpha-oxidation of phytanoyl-CoA (branched chain f.a.))
    • -no alpha-oxidation=>high phytanic acid levels in blood and tissues
    • -severe neurological problems: cerebellar dysfunction, blindness, deafness
  25. Differences between f.a. oxidation and synthesis:
    • 1) Reactions
    •        -B-oxidation: oxidation, hydration, oxidation, cleavage
    •        -synthesis: condensation, reduction, dehydration, reduction
    • 2) 2C unit 
    •        -B-oxidation: acetyl-CoA
    •        -synthesis: malonyl-CoA
    • 3) Carrier
    •        -B-oxidation: CoA
    •        -synthesis: Acyl Carrier Protein (ACP)
    • 4) Location
    •        -B-oxidation: mitochondria
    •        -synthesis: cytosol
  26. Enzyme that is pivotal in regulating between FA synthesis and B-oxidation
    • Acetyl-CoA Carboxylase 
    • -1st reaction: adds CO2 to biotin
    • -2nd reaction: transfers CO2 to acetyl-CoA=>malonyl CoA=>FA synthesis
  27. Two Ketone bodies:
    • -acetoacetate
    • -Beta-hydroxybutyrate
  28. What causes Holoproencephalopathy (HPE)?
    • -mutation in SHH
    • -deficiency of cholesterol
  29. Smith-Lemli-Opitz Syndrome
    • -2/3 toe syndactyly diagnostic feature
    • -mutation in 7-dehydrocholesterol reductase=>cholesterol deficiency=>disrupts SHH function=>HPE
  30. Desmosterolosis
    -decreased cholesterol and/or increased desmosterol disrupt SHH function
  31. Major Apoproteins: tissue source, lipoprotein distribution, metabolic function
    • ApoA-1:
    • -Tissue Source: Intestine/Liver
    • -Lipoprotein distribution: HDL
    • -Metabolic function: activates LCAT; structural component of HDL
    • ApoB-48: 
    • -Tissue Source: Intestine
    • -Lipoprotein distribution: Chylomicrons
    • -Metabolic function: assembly and secretion of chylomicrons from intestinal mucosa
    • ApoB-100: 
    • -Tissue Source: Liver
    • -Lipoprotein distribution: VLDL, IDL, LDL
    • -Metabolic function: VLDL assembly and secretion; structural protein of VLDL, IDL, LDL; ligand for LDL receptor
    • ApoC-2: 
    • -Tissue Source: Liver
    • -Lipoprotein distribution: Chylomicrons, VLDL, IDL, HDL
    • -Metabolic function: activates lipoprotein lipase
    • ApoE:
    • -Tissue Source: Liver
    • -Lipoprotein distribution: Chylomicrons remnants, VLDL, IDL, HDL
    • -Metabolic function: ligand for binding several lipoproteins to the LDL receptor, and to the LDL receptor related protein
  32. Abetalipoproteinemia
    • -deficient in Microsomal Triglyceride Transer Protein (MTTP)
    • -incapable of making CM, VLDL (LDL) lipoproteins=>severe malabsorption of dietary fats and fat-soluble vitamins
  33. Niemann-Pick Type C Disease
    -mutations in NPC1 and NPC2, both involved in release of cholesterol from late endosomes and lysosomes=>cholesterol depletion from PM=>↑LDL receptors=>↑LDL uptake=>cholesterol build-up in CNS, liver, and spleen=>spenolmegaly, hepatomegaly
  34. Tangier Disease
    • -defect in reverse cholesterol transport, loss of ABCA1 transporter frunction
    • -cholesterol-poor HDL particles cleared in kidney=>build-up of cholesterol in peripheral tissues
    • -CM and VLDL do not obtain normal ApoC-2 levels to activate LPL=>hypertriglyceridemai
    • -impaired LDL formation from VLDL
    • -orange colored tonsils is characteristic
  35. Atherogenic Dyslipidemia
    • Combination of 3 abnormalities in plasma lipoproteins:
    • -increase VLDL
    • -decrease HDL
    • -increase LDL

    -dyslipidemia profile is major increase for CHD
  36. Steps in Cholesterol Synthesis
    • 1. Three acetyl-CoA’s are condensed into 6C mevalonate.
    • 2. Mevalonate is converted into a 5C activated isoprene.
    • 3. Six 5C isoprenes are condensed into a 30C squalene and modified to form 27C cholesterol.
    • 4. Cholesterol can be further modified to form other steroid species by adding different functional groups
  37. Statins
    HMG CoA reductase inhibitors=>lowers cholesterol levels in body
  38. Regulation of HMG CoA reductase
    • 1. Sterol-dependent expression of HMG-CoA reductase by SREBP-2.
    • 2. Sterol-independent phosphorylation of HMG-CoA reductase by AMP-activated protein kinase (energy charge).
    • 3. Sterol accelerated proteolysis of HMG-CoA reductase.
    • 4. Hormonal regulation by insulin and thyroxine (upregulate expression) and glucagon and glucocorticoids (downregulate expression).
  39. Pharmacological inhibition of HMG CoA reductase
    • -HMG-CoA is reduced by HMG-CoA reductase to form mevalonate, the first commited step in cholesterol biosynthesis. Ex of statins:
    • 1)Chemical name: Atorvastatin 
    •    Trade name: Lipitor 
    • 2)Chemical name: Mevacor 
    •    Trade name: Lovastatin  
    • 3)Chemical name: Pravastatin 
    •    Trade name: Pravachol
    • 4)Chemical name: Simvastatin 
    •    Trade name: Zocor
  40. Thiazolidinediones:
    • -a class of glucocorticoid derivatives 
    • -used to treat type 2 diabetes
    • -Thiazolidinediones increase the rate of glyceroneogenesis, thus increasing the resynthesis of TGs in adipose tissue, and reducing the amount of fFAs in the blood. This also has a desired effect to decrease insulin resistance
  41. Sickle Cell Anemia
    • -mutation in 6th a.a in Beta-globin chain, mutating a glutamic acid to a valine
    • -in Hemoglobin C Disease, glutamic acid is mutated into a lysine
    • -treatment is drug Hydroxyurea, which laters maturation of erythoid precursors and indirectly promotes the expression of fetal Hb. HbF is incorporated into HbS, inhibiting HbS synthesis into strands, generating HbS strands that are less likely to form fibers.
  42. Methemoglobinemia
    • -oxidation of Fe+2 to Fe+3 inhibits the ability of Hb to deliver O2 to the tissues
    • -can be caused by nitrates and other oxidizing drugs
    • -or mutations in NADH-cytochrome B5 reductase or genetic deficiencies of enzymes that reduce the levels of NADH in the cell (eg, pyruvate kinase)
  43. Thalassemia
    • -mutation, either deletion or point, that diminishes or eliminates the production of one of the two chains of hemoglobin
    • -alpha Thalassemia occurs on chromosome 16
    • -beta Thalassemia occurs on chromosome 11
    • -caused by mutations within the regulatory regions, as well as the coding regions
  44. Types of Hemoglobin
    • -Adult Hb (HbA) α2β2 >95% of adult Hb
    • -Adult Hb (HbA2) α2δ2 <3% of adult Hb
    • -Fetal Hb (HbF) α2γ2 predominant in fetal development; also <3% of adult Hb
    • -Embryonic Hb (HbE) ε2ζ2 early in embryonic development (3 to ~9 weeks gestation)
  45. Imatinib
    • -used to treat CML (chronic myelgenous leukemia)
    • -bcr-abl, a tyrosine kinase, that phosphorylates and causes proliferation is inactivated by the binding of imatinib
  46. Difference between AML and CML
    • -AML is a blockage in the differentiation of myelocytes, stopping the presence of any mature cells
    • -CML is a overall increase in proliferation of myelocytes, both mature and immature
  47. Deficiency of vWF
    • Circulating forms of vWF produced by endothelial cells bind to and stabilize inactive Factor VIII in circulation. In the absence of vWF, Factor VIII is rapidly degraded=>bleeding
    • -autosomal recessive
  48. Hemophilia A
    • -characterized by a lack of Factor VIII
    • -X-linked
  49. Serine Proteases and their Associated Co-Factors of the Blood Coagulation Cascade
    • Protease         Associated Factor
    • Factor VII         Tissue Factor (Factor III)
    • Factor IXa         Factor VIIIa
    • Factor Xa          Factor Va
    • Factor IIa (thrombin) Thrombomodulin
    • Protein Ca        Protein S
  50. Tissue factor pathway inhibitor (or TFPI)
    -can reversibly inhibit Factor Xa (Xa)
  51. What is the mechanism by which low dose aspirin inhibits the process of blood coagulation?
    • Inhibits the synthesis of thromboxane A2 by platelets
    • -thromboxane A2, a vasoconstrictor that activates more GP2a/2b
  52. Thrombin activation
    • -Factor 5a + Factor 10a convert prothrombin to thrombin 
    • -Thrombin converts Fibrinogen to Fibrin
    • -Thrombin activates 13a, which converts soft clot to cross-linked clot
  53. Thrombin positive feedback
    Activates 5a and 8a, which accelerates its own activation
  54. Warfarin
    -vitamin K analogue that reduces gamma-carboxylation, preventing localization of clots
  55. Non-covalent inhibition of Coagulation process:
    • -tissue factor pathway inhibitor (TFPI) binds to Factors 7a and 10a
    • -Antithrombin 3 (is a serpin which is a serine protein inhibitor) binds to Factors 2a,9a,10a,11a
    • -Proteins Z and ZPI
  56. Covalent inhibition of Coagulation process:
    Activated protein C
  57. Factor 5 Leiden
    • -hypercoagulability (thrombophilia)
    • -Leiden variant of Factor 5 can not be inactivated by Protein C
  58. The players in fibrinolysis
    • -Plasminogen=inactive plasmin
    • -Plasmin=active protease that hydrolyzes fibrin
    • -tPA(tissue plasminogen activator)=hydrolyzes plasminogen to plasmin, binds strongly to clot
    • -alpha-2-antiplasmin=protein inhibitor of plasmin
    • -PAI(plasminogen activator inhibitor)=inhibits plasmin activators
    • -scu-PA(urokinase)=circulating serum protein that also hydrolyzes plasminogen to plasmin, but does not localize to the clot
    • -Streptokinase=bacterial protein that happens to bind to the plasminogen and triggers a conformational change that activates the plasminogen
  59. Multiple Myeloma
    • -cancer of plasma cells, a subset of B cells that secrete immunoglobins
    • -symptoms include elevated Ca2+,renal failure, anemia, and bone lesions
    • -high concentration of monoclonal antibodies in serum and secrete monoclonal light chains called Bence Jones proteins in their urine
  60. Convention for naming monoclonal antibodies
    • 1)Murine Antibodies: -momab
    • 2)Chimeric Antibodies: -ximab
    • 3)Humanized Antibodies: -zumab
    • 4)Fully Human Antibodies: -mumab
  61. Types of Immunoglobins:
    • IgG: majority of immune response
    • IgA: mucosal secretions (tears, saliva)
    • IgM: part of early immune response, later transform into IgG
    • IgD: function is to signal the B cells to be activated
    • IgE: attacks parasites, involved in allergies
  62. Type 1 Nuclear Receptor
    • -steroid-based (estrogens, androgens, glucocorticoids, mineralcorticoids)
    • -without ligand, exists in cytosol associated with heat shock proteins (HSP)
    • -with ligand, loss of HSP and inhibition, nuclear translocation, DNA binding and recruitment of activators=>euchromatin and transcription
    • -receptors bind as homodimers to inverted repeat response elements.
  63. Type 2 Nuclear Receptor
    • -Vit D, Retinoic acid, Thyroid
    • -without ligand, receptor bound to DNA, associated with corepressors=>supresses trancription
    • -with ligand, loss of corepressors, recruitment of coactivators=>euchromatin and transcription
    • -receptors bind as heterodimers with RXR to direct repeat response elements
  64. Other signaling pathways:
    • 1) Wnt=>Frizzled
    • 2) SHH=>patched and smoothin
    • 3) Stress=>NF-kB=>has kinase activity
    • 4) Notch+Delta, MMP=>cell to cell signaling
    • 4) Matrix Metalloproteases (MMP) cleave GFs=>RTK. Mutation can lead to cancer.
  65. PKB functions:
    • -phosphorylates and inactivates pro-apoptotic proteins
    • -prevents transcription of pro-apoptotic proteins
    • -promotes glucose uptake and storage
  66. PTEN and PKB
    • -PTEN inactivates PKB, promoting apoptosis
    • -PTEN becomes deleted in multiple advanced stage cancers
  67. Tamoxifen
    -in Estrogen receptor positive breast cancer, (ER positive), tamoxifen is estrogen analogue that inhibits estrogen receptor-has stimulatory affect in uterine endometrial cells=>increased risk of uterine cancer
  68. CDKIs (Cylcin dependent kinase inhibitors)
    • 2 families: INK4 and CIP/KIP
    • -INK4: p15,p16,p18,p19
    • -CIP/KIP: p21,p27,p57
    • -know the specificity of the INK4 CDKIs for CDK4 or CDK6, while CIP/KIP CDKIs can inhibit any CDK complex
    • -CIP/KIP members bind in a complex of the CDK and the cyclin, and cause inhibition. INK4 members displace the cyclin from the CDK complex, thereby preventing activation of the CDK subunit by its associated cyclin
  69. Checkpoints, CDK, cyclin and CDKI
    • Checkpoint      CDK      Cyclin    CDKI
    • Mid-G1            4/6         D  CIP/KIP or INK4
    • G1/S                 2          E    CIP/KIP
    • S                      2          A    CIP/KIP
    • G2-M                1          B    CIP/KIP
  70. Important:
    • -CDK levels do not change throughout cell cycle, only cyclins or CDKI
    • -cdc25 removes inhibitory phosphates=>prevents CDK from becoming active
  71. Essential traits of a successful tumor:
    • -self sufficiency in growth signals
    • -insensitivity to antigrowth signals
    • -evasion of apoptosis
    • -limitless replicative potential
    • -tissue invasion and metastasis
    • -sustained angiogenesis
  72. Proto-oncogenes vs tumor suppressors
    • Proto-oncogenes: mutations are genetically dominant
    • Tumor suppressors: mutations are genetically recessive
  73. Anti-Apoptotic:
    Bcl-2, Bcl-XL and IAPs(inhibitors of apoptotic proteins)
  74. Pro-apoptotic:
    Bax, Bid, Bad and SMAC/Diablo
Card Set
Block 3 - Cardiac
Block 3 - Cardiac
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