Hypertension and Atherosclerosis

Question 1

What are the organs susceptible to hypertensive end organ damage?

Answer 1

1) Heart
2) Kidney; Glomerulopathy
3) Brain; Encephalopathy
4) Eye; Retinopathy

Question 2

Describe 2 factors determining the blood pressure.

Answer 2

Systemic blood volume: a lot of water in a balloon increases the pressure

Systemic vascular resistance; narrow blood vessels. Related to systolic.

Question 3

What are the receptors for sympathetic and parasympathetic innervations, and how do they affect vascular tone?

Answer 3

Sympathetic (fight or flight): α adrenergic receptor - smooth muscle contractors

Parasympathetic (relax): M (muscarinic) receptors at endothelium that stimulates the endothelial cells to secrete nitric oxide (NO) to make the muscles relax

Affect vascular tone by controlling the afterload

Question 4

How does Renin-Angiotensin system (RAS) affect circulatory volume?

Answer 4

Affects how the kidney reabsorbs water and salt, thus leading to an increase in the cardial preload to increase blood pressure

Question 5

Can you tell the story of how the first ‘designer drug’ Captopril was developed?

Answer 5

Bradykinin: inflammatory mediator and potent vasodilator. Inactivated in pulmonary circulation by Bradykinin inactivating enzyme.

Found BPF from snake venom that inhibits the Bradykinin inactivating enzyme. Inactivation of this inactivating enzyme leads to increase in Bradykinin and vascular collapes via vasodilation and leaking of blood.

Angiotensin I is converted to Angiotensin II by pulmonary cleavage of C terminal. Bradykinin is also inactivated via pulmonary cleavage of last two peptides. Therefore investigators wanted to know if BPF could inactivate ACE, thus leading to a decrease in angiotensin conversion from I to II (i.e. angiotensin activation). This would thus lead to a decrease in blood pressure.

Used blood bathed organ.

Designer drug part: Structure of snake venom molecule was difficult to synthesize at the time and not orally administrable. Compared two peptide exopeptidases. Looked at something that would interact with ACE to prevent angiotensin activation.

Question 6

List 2 diagnostic tests for acute myocardial infarction.

Answer 6

1) EKG: Look for abnormal muscle contractions
2) Urine/Saliva test: look for serum cardiac enzymes (troponin, creatine phosphokinase (CK-MB)
3) Chest X-ray: Just to rule out other causes of sudden onset chest pain

Question 7

Which cell type plays the most major role in atherosclerosis?

Answer 7

Macrophage, eats lipids and eventually forms foam cells.

LDL (bad cholesterol) is uptaken by foam cells, whereas HDL (good cholesterol) is released by foam cells and HDL then gets processed by the liver

Question 8

Atherosclerosis

Answer 8

Thickening of artery with plaque

Question 9

Angiotensin converting enzyme (ACE)

Answer 9

Cleaves c-terminal dipeptide of angiotensin I.

ACE, is a central component of the renin-angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasoconstrictor angiotensin II. Therefore, ACE indirectly increases blood pressure by causing blood vessels to constrict.

Question 10

Describe 3 stages of atherosclerotic plaque progression.

Answer 10

1) Early lesion - fatty streak: A little bit of foam cells and some fat, but all of this is reversible.
2) Lesion progression: Macrophages are forming a lot of foam cells and secrete cytokines to attract smooth muscle cells and blood clotting factors to lumen.
3) Plaque rupture and thrombosis: Foam cells are undergoing necrosis and blood clotting is occurring. Eventually this process will block the artery.

Question 11

Describe 2 major mechanisms of atherosclerotic plaque regression.

Answer 11

1) Excrete lipids to HDLs (lipid outflux)

2) The macrophages themselves can leave the lesion

Question 12

Describe the mechanism of lipoprotein efflux from lipid containing macrophages.

Answer 12

Upregulation of certain transporters that takes care of intracellular lipids and shuttles them back to HDLs.

LSR/RXR are transcription factors that upregulate these transporters (ABCA1/ABCG1).

Question 13

T/F: Activation of α adrenergic receptor results in vasoconstriction.

Answer 13

True, α adrenergic receptors are on the smooth muscle cells and lead to muscular constriction.

Question 14

T/F: Muscarinic receptors at vascular smooth muscles induce nitric oxide secretion.

Answer 14

False, endothelial cells secrete nitric oxide.

Question 15

T/F: Angiotensin I is activated in the pulmonary circulation.

Answer 15

True, converted by ACE.

Question 16

T/F: Angiotensin II inhibits renal tubular reabsorption.

Answer 16

False, angiotensin II increases cardial preload. Inhibiting this peptide has an anti-hypertensive effect.

Question 17

Infarction

Answer 17

Death of tissues due to blockage of blood flow

Question 18

Thrombosis

Answer 18

Formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system

Question 19

Therapeutic perspectives to induce cardiac plaque regression.

Answer 19

1) Promote lipid efflux mechanism: LXR (TF that promotes lipid transporters for HDL secretion) agonists. Can also induce ABCA1/ABCG1 expression levels by inhibiting repressive miRs.
2) Reduce the inflammatory state of macrophage: Macrophage polarization (less M1 - aggressive/damaging; more M2 - less aggressive and more easily regulatted). Anti inflammatory factors (IL-10)