atherosclerosis Flashcards Preview

Y elective pathobiochemistry > atherosclerosis > Flashcards

Flashcards in atherosclerosis Deck (27)
1

Things that can cause vascular damage leading to atherosclerosis

High cholseterol
Turbulent blood flow
Shearing forces
sdLDL
oxLDL

Chronic Inflammation, possibly some viruses, C. pneumonia

2

Cholesterol uptake transporters in the intestine

proximal jejunum

NPC1

NPC1L1

3

ER transporter of cholesterol

ACAT
forms cholesterol esters from cholesterol acyl coa cholesterol transport protein.

4

What transcription factor regulates liver synthesis and export of cholesterol?

LXR
Liver X Receptor

5

What regulates Bile acid uptake in the ileum?

IBAT
IBABP

Ilial bile acit transporter
ileal bile acid binding protein

both are FXR regulated

6

Which HDL is taken back up by the liver?

HDL 2

7

What regulates cholestrol synthesis?

HMG-CoA reductase

8

What regulates bile/cholesterol transport into the bile canaliculi?

ABC transporters,
ABCA1
ABCG1

BSEP

9

What does LXR do

LXR stimulates bile acid synthesis,
by activating 7-alpha-hydroxylase

Increases ABCA1, ABCG1 activity, increased bile transport

Activaters CETP
Cholesterol Ester transfer protein,
Increasing cholesterol transfer into HDLs
Mutations in CETP increase atherosclerosis, and increasing activity increases Cholesterol clearance

10

What do insigs do?

INSIGs bind to SCAPs and prevent them from activating sterol synthesis.

11

What does FXR do?

Increases BSEP activity, increased Bile salt export pump.

Increases SHP activity, which inhibits LXR

12

How is cholesterol synthesis induced by low cholesterol, in the liver?

SREBP-2, an ER-integral membrane protein

SREBP-2 binds to SCAP in the ER membrane,

SREBP-2-SCAP complex moves to the golgi and is cleaved

SREBP-2 is cleaved into fragments which go to the nucleus and bind DNA SRE, inducing increases HMG-CoA synthesis.

Low cholesterol also increases LDL-receptor expression to obtain fats.

13

How is Cholesterol taken up by peripheral cells?

By the LDL receptor

14

How is cholesterol exretyed by peripheral cells?

by ABCA1
ABCG1,5,8

Into HDLs

Under control of the LXR transcription factor.

15

Antithrombotic mediators of endothelial cells

PGI2

ADP

16

Anticoagulant effect of endothelial cells

Thrombomodulin
Heparin

17

Fibrinolytic effect of endothelial cells

tPA

PAI-1

18

Cytokines establising smooth muscle tone of the Aorta

NO

Bradykinin

19

Anti-inflammatory effect of endothelial cells

Inhibition of adhesion and migration of leukocytes.

20

Changes in expression by dysfunctional endothelial cells

Increased CRP

decreased eNOS

decreased NO

Increased VCAM-1,
more leukocyte adhesion

Increased MCP-1
monocyte and macrophage chemotaxis

21

Possible sources of ROS

Macrophages
NADH/NADPH oxidase,
Xanthine oxidase
iNOS

Endothelial cells
eNOS

Lipoproteins
sdLDL
has low affinity for LDL receptor and longer half life, thus more oxLDL.

Lipid peroxidation
peroxidation of plasma membrane

peroxidation of LDL
oxLDL

22

How do macrophages damage endothelium and contribute to atheroma

Metalloproteases
ROS

Trapping in the endothelium

Foam cell generation

sdLDL and oxLDL accumulation,

Cholesterin crystals

necrosis

23

Components of an atheroma

Dysfunctional/damaged endothelium overlying

Macrophages, Foam cells,
Monocytes
Fibroblasts
Cholesterol
Cholesterin crystals
Necrotic core
Apotpotic cells
Calcified cholesterols
Smooth muscle cells

24

Atherosclerosis risk factors

High cholesterol,
High LDL

smoking
Hypertension
B6 vitamin deficiency
Hyperhomocysteinemia

Obesity

Diabetes
Hyperglyceima
Hypertriglyceridemia

25

What causes familial hypercholesterolemia

LDL receptor mutations

ApoA1 mutation, low HDL

LCAT mutation

ABCA1

Cyp27

LPL deficiency is NOT a risk factor.

26

Medical treatments for atherosclerosis

Statins inhibit HMG-CoA reductase

NPC1L1 inhibitors

VLDL exocytosis inhibitors

PPAR activators, called fibrates.

27

PPARalpha

inhibits SREBP-1 and SREBP-2 activation, thus inhibiting FA synthesis and Cholesterol synthesis

Also inhibits Malic enzyme, inhibiting conversion of citrate to pyruvate and NADPH for cholesterol synthesis.

Decreases LDL receptor expression