Pulmonary hypertension 1 Flashcards
what is pulmonary hypertension?
High blood pressure in the lungs
Pulmonary hypertension lungs: Narrowing of pulmonary arteries, right ventricular hypertrophy and can lead to right heart failure
What is done to confirm the diagnosis of PAH?
Right heart catheterisation is required to confirm the diagnosis of PAH.
PAH is defined by:
- mPAP more than or equal to 25mmHg at rest
- PCWP less than or equal to 15mmHg
- Different to systemic BP (where you can even measure yourself)–> measuring pulmonary hypertension is more invasive–> have to get into the pulmonary vessels
- This is done by right heart catheterization: can enter through femoral vein or internal jugular vein- depends on the individual patient
describe the vascular remodelling that occurs in PH
- PH is characterised by sustained vasoconstriction and a progressive obliteration of small resistance pulmonary arteries and arterioles
- Medial thickening, intimal fibrosis and the formation of angioproliferative (plexiform) lesions
- Inflammation and endothelial dysfunction and pulmonary artery endothelial cell apoptosis/dysfunction are thought to play an important early role in disease pathogenesis
- Subsequent proliferation and migration of medial cells including smooth muscle cells, fibroblasts and PA-EC drives the pulmonary vascular remodelling
What is PH diagnosed as?
Diagnosed as >25mmHg pulmonary arterial pressure (normal = 14)
what are the range of diseases that can cause PH?
o Genetic predisposition
o drugs
o Heart diseases e.g. aortic valve disease, left heart failure, mitral valve disease
o Liver diseases
o Rheumatic disorders
o Lung conditions e.g. COPD, pulmonary fibrosis
o Clotting issues e.g. thromboembolic disease
o High altitude living- low O2 saturation
Pulmonary hypertension is found in multiple clinical conditions and is clinically classified into 5 groups. Describe Group 1
Group 1: Pulmonary arterial hypertension
• Rare disorder (15-20 cases per million)
• Heritable accounts for 15-20% of cases (known mutations)
– mutations in bone morphogenetic protein (BMP) type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-β superfamily
o a growth factor like pathway therefore driving cell growth and cell proliferation
o therefore, mutations in BMPR-II= see abnormal and increase responses to GFs
– Leads to abnormal growth responses to TGF-β
• 2-4 times more common in women
• Mean age of onset 45 y
• Prevalence higher in at risk groups (HIV, sickle cell, parasitic infections [developing world])
describe vascular remodelling which occurs in PAH
Healthy vessel to diseased vessed:
Diseased–> remodelled vessel with significantly reduced lumen, increased proliferation of all cell types; seen in endothelial, smooth muscle and fibroblast layers.
Dysregulation of vascular tone – increased vasoconstriction due to alteration of endothelial cell secretion (increased expression of vasoconstrictors–>):
o Endothelin-1, (a target for inhibiting this disease)
o Alteration in other classic pathways that induce vasodilation (NO pathway, PGI2 (prostaglandin signalling etc)
o K+ and Ca2+ channels
o Serotonin
o PDE
o Significant alteration in vascular tone
what subsequently happens when vascular tone is dysregulated during PAH?
- This Subsequently affects the proliferation of cells= abnormal proliferation due to… o TGF-beta, BMP o (+ other growth factors) PDGF, FGF o Transcription factors (Notch 3) o Metabolic changes o MMPs o Cytokines and chemokines
= increased resistance + reduced flow–>likely to induce hypoxia
- Hypoxia- induced vasomotion and remodelling
o Low oxygen tension can drive proliferation of cells
o And hypoxia subsequently occurs due to reduced flow in vessel
o Low oxygen tension activates pathways and TFs in the cell that affects which genes get expressed in cell
o HIF- hypoxia induced factor changes metabolic signature of vessel which can exacerbate disease
• HIF gets stabilised= activates genes that changes the metabolic signature of the vessel + can exacerbate disease.
describe the growth factor signalling which occurs in PAH
GF signalling in PAH causes increased proliferation, survival and migration of the cell
- PDGF or FGF binds to its receptor–>dimerises–> activates downstream pathways
o Increased transcription through RAS/MEK pathway to activate transcription factors that increase migration
o PI3K/AKT pathway increases survival of the cells
o JAK/STAT pathway activates proliferation - This would occur in fibroblasts and smooth muscle cells
describe inflammation-mediated vascular remodelling in PAH
Lesions show huge infiltration of immune cells & significant narrowing of arteries Immune cells upregulated and infiltrated in PAH response:
• Lots of cytokines released to activate T cells
• See a lot of macrophages infiltrating the vessel as well
• T-REG cells, T cells, macrophages etc then activate cytokines, chemokines and growth factors
• i.e lots of exacerbation from immune cell
what causes Group 3 PH?
Group 3 PH due to lung diseases (e.g. COPD) and hypoxia:
chronic lung disease can lead to prolonged exposure to alveolar hypoxia–> remodelling of pulmonary vasculature–> increased pulmonary arterial pressure and right ventricular hypertrophy.
HIF mediates the hypoxic response in group 3 PH. describe HIX
HIF (hypoxic inducible factor) is a transcription factor that regulates hypoxia induced gene transcription.
It is a heterodimer: HIF-1a and HIF-1beta subunits.
you can also have hIF-2a (i.e. 2 main alpha subunits)
within the alpha subunit, there are a number of domains:
- These domains have important regulatory function but also activity for the - (HIF1alpha or HIF2alpha)–> either of those will then bind to a HIF-1beta binding partner
- HIF-1beta is constitutively expressed (i.e. present in the nucleus of cells–> not regulated by the oxygen tension= only the alpha subunit is regulated by oxygen levels)
HIF-1/2a levels are tightly regulated by O2 and are degraded in normoxia, but stabilised in hypoxia i.e. the oxygen levels ultimately determine if the transcription factor gets activated or not.
C terminus: certain residues that get hydroxylated i.e. OH group binds to proline residues (e.g. P564)
N terminus: PAS domains and bHLH (basic helix loop helix domains)–> Important for binding dimerization of both subunits
Only the a subunit of HIF is regulated by O2 levels not B
bHLH= basic helix loop helix PAS = per-arnt-sim TAD= transactivation domain C-terminus or N-terminus ODD= oxidation dependent degradation domain
Either HIF-1alpha or HIF-1beta binds and activates HIF-1beta= activate transcription
describe HIF-1 regulation by post-translational modification during normoxia
HIF-1 is constantly being synthesised and degrade inside the cell
Normoxia –
• 3 proline hydroxylase enzymes (PHDs) in the presence of O2 and cofactors hydroxylate HIF-1a
• = Recognition by von Hippel Lindau (VHL) protein – an E3 ligase which targets HIF for degradation via ubiquitination (so it is recognised and degraded by proteasome)
describe HIF-1 regulation by post-translational modification during hypoxia
• Hypoxia –
• PHDs inactive (As require O2), HIF translocates to nucleus (as it has a nuclear translocation signal)
o HIF-1a AND HIF-1b dimerising= recruit other cofactors and sits on hypoxic response element (HPE) present in HIF target genes–>
• Activates genes involved in angiogenesis, cell migration and (glucose) metabolism
Can see erythropoiesis (new red blood cell production) in the diagram too–> to counteract the hypoxia
