2011肺动脉高压发生的分子机制(研究生讲座)
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undue dyspnea or fatigue, chest pain or near syncope.
Class IV – Patients with pulmonary hypertension with
inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
THE EVALUATION OF MILD PULMONARY HYPERTENSION
High Risk Individuals Individuals who are asymptomatic but at high risk of developing pulmonary hypertension should have a Doppler echocardiographic exam repeated in six months. Asymptomatic Individuals (Incidental Discovery) It is
Pulmonary hypertension
※ Definition and Classification ※ Pathogenesis ※ Animal model
Definition
mPAP >25mmHg(rest) or >30 mmHg (exercise)-----based on Hypertension catheter-derived assessment. Mild pulmonary hypertension is defined as a systolic pulmonary ? Pulmonary hypertension artery pressure of 40-50 mmHg, which corresponds to a tricuspid regurgitant velocity on Doppler echocardiography of 2.8-3.5 m/sec
cellular and molecular mechanisms of pulmonary hypertension
LI Zhi Chao
PH is a multifactorial disease characterized by
a progressive increase in pulmonary vascular
Angiogenic factors
Angiogenesis markers such as VEGF and HIF-1
have been shown to be expressed in the
plexiform lesions of patients with severe PAH
HIF-1
near syncope.
Class II – Patients with pulmonary hypertension resulting in
slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.
Functional Assessment
Class I – Patients with pulmonary hypertension but without
resulting limitation of physical activity. Ordinary physical
activity does not cause undue dyspnea or fatigue, chest pain or
VEGF
NOS
NO
Caveolin-1
angiogenasis
P27Kip1 Is Important in Modulating
Pulmonary Artery Smooth Muscle Cell Proliferation
Western blot analysis of 21Cip1/Waf1, p27Kip1, cdk2, and proliferating cell nuclear antigen (PCNA) expression in rat PASMCs during 5 d of 10% FBS.
Acute hypoxia
K+ channel activity membrane depolarization Ca2+ influx in PASMC
HPV
Chronic hypoxia downregulates K+ channel expression in PASMC
IK(V) = N × iK(V) × Popen
Class III – Patients with pulmonary hypertension
resulting in marked limitation of physical activity. They
are comfortable at rest. Less than ordinary activity causes
recommended that a Doppler echocardiogram be repeated in six months along with a detailed history and physical examination.
Symptomatic Individuals It is recommended that signs of
inositol 1 4,5 triphosphate － induced calcium release
Ryanodine
Plasma membrane Ca2+-ATPase
MAPK II， c-foc are Ca 2+ dependent AP-1,GF systhesis
Relevant Pathways in the Pathogenesis of Pulmonary Arterial Hypertension
The role of 5-HT receptors and transporters
5-HT is a vasoconstrictor and a mitogen
Upregulated 5-HTT and increased 5-HT are
associated with pulmonary hypertension
Pathogenesis
Mechanisms of PH
Vascular mechanisms of PH
Pulmonary arterial vasoconstriction Pulmonary arterial wall remodeling
Pulmonary arterial vasoconstriction
Genetics of Pulmonary Arterial Hypertension
BMPR2(bone morphogenetic protein receptor 2) 5-HTT (serotonin transporter gene),whose LL polymorphism (2 long alleles) ALK-1 (activin receptor-like kinase 1) endoglin ( associated with hereditary hemorrhagic telangiectasia
Different response between PA and SA
Endothelial dysfunction in pulmonary hypertension
Maintenance of normal vascular structure
and function. heterogeneity Endothelial barrier function Endothelial cells are also responsible for producing a wide array of growth factors and vasoactive mediators
Pulmonary arterial wall remodeling
?
K+ efflux and PASMC apoptosis: role in vascular remodeling
vasoconstriction、Remodeling and Calcium
voltage dependence Ca2+ channel receptor operated Ca2+ channel calcium release activated calcium channel sarco/endoplas mic reticulum Ca2+-ATPase
Pulmonary arterial hypertension (PAH)； Pulmonary hypertension due to left heart
disease； Pulmonary hypertension due to lung diseases and hypoxemia； Chronic thromboembolic pulmonary hypertension; PH with unclear or multifactorial mechanisms
Role of bone morphogenetic protein receptor type II (BMP-R2) gene mutations
BMP-R2 突变或功能障碍
Bcl－2
Decreased KV channel activity leads to inhibition of apoptotic volume decrease and apoptosis
number of channels (N) the unitary current amplitude of each channel (iK(V)) the probability that the channels are in the open state (Popen)
NADPH oxidase
resistance caused by vasoconstriction, vascular
cell proliferation and obliteration of pulmonary
microvasculature. These processes lead to right
heart failure.
5-HTT gene polymorphism in patientassium Channels Inhibition of the voltage regulated (Kv) potassium channel by hypoxia or drugs can produce vasoconstriction and has been described in pulmonary artery smooth muscle cells harvested from patients with PPH.
pulmonary hypertension warrant right heart catheterization for confirmation of the hemodynamic findings.
(2008)
Updated Classification of
Pulmonary Hypertension(2009)
Class IV – Patients with pulmonary hypertension with
inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
THE EVALUATION OF MILD PULMONARY HYPERTENSION
High Risk Individuals Individuals who are asymptomatic but at high risk of developing pulmonary hypertension should have a Doppler echocardiographic exam repeated in six months. Asymptomatic Individuals (Incidental Discovery) It is
Pulmonary hypertension
※ Definition and Classification ※ Pathogenesis ※ Animal model
Definition
mPAP >25mmHg(rest) or >30 mmHg (exercise)-----based on Hypertension catheter-derived assessment. Mild pulmonary hypertension is defined as a systolic pulmonary ? Pulmonary hypertension artery pressure of 40-50 mmHg, which corresponds to a tricuspid regurgitant velocity on Doppler echocardiography of 2.8-3.5 m/sec
cellular and molecular mechanisms of pulmonary hypertension
LI Zhi Chao
PH is a multifactorial disease characterized by
a progressive increase in pulmonary vascular
Angiogenic factors
Angiogenesis markers such as VEGF and HIF-1
have been shown to be expressed in the
plexiform lesions of patients with severe PAH
HIF-1
near syncope.
Class II – Patients with pulmonary hypertension resulting in
slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.
Functional Assessment
Class I – Patients with pulmonary hypertension but without
resulting limitation of physical activity. Ordinary physical
activity does not cause undue dyspnea or fatigue, chest pain or
VEGF
NOS
NO
Caveolin-1
angiogenasis
P27Kip1 Is Important in Modulating
Pulmonary Artery Smooth Muscle Cell Proliferation
Western blot analysis of 21Cip1/Waf1, p27Kip1, cdk2, and proliferating cell nuclear antigen (PCNA) expression in rat PASMCs during 5 d of 10% FBS.
Acute hypoxia
K+ channel activity membrane depolarization Ca2+ influx in PASMC
HPV
Chronic hypoxia downregulates K+ channel expression in PASMC
IK(V) = N × iK(V) × Popen
Class III – Patients with pulmonary hypertension
resulting in marked limitation of physical activity. They
are comfortable at rest. Less than ordinary activity causes
recommended that a Doppler echocardiogram be repeated in six months along with a detailed history and physical examination.
Symptomatic Individuals It is recommended that signs of
inositol 1 4,5 triphosphate － induced calcium release
Ryanodine
Plasma membrane Ca2+-ATPase
MAPK II， c-foc are Ca 2+ dependent AP-1,GF systhesis
Relevant Pathways in the Pathogenesis of Pulmonary Arterial Hypertension
The role of 5-HT receptors and transporters
5-HT is a vasoconstrictor and a mitogen
Upregulated 5-HTT and increased 5-HT are
associated with pulmonary hypertension
Pathogenesis
Mechanisms of PH
Vascular mechanisms of PH
Pulmonary arterial vasoconstriction Pulmonary arterial wall remodeling
Pulmonary arterial vasoconstriction
Genetics of Pulmonary Arterial Hypertension
BMPR2(bone morphogenetic protein receptor 2) 5-HTT (serotonin transporter gene),whose LL polymorphism (2 long alleles) ALK-1 (activin receptor-like kinase 1) endoglin ( associated with hereditary hemorrhagic telangiectasia
Different response between PA and SA
Endothelial dysfunction in pulmonary hypertension
Maintenance of normal vascular structure
and function. heterogeneity Endothelial barrier function Endothelial cells are also responsible for producing a wide array of growth factors and vasoactive mediators
Pulmonary arterial wall remodeling
?
K+ efflux and PASMC apoptosis: role in vascular remodeling
vasoconstriction、Remodeling and Calcium
voltage dependence Ca2+ channel receptor operated Ca2+ channel calcium release activated calcium channel sarco/endoplas mic reticulum Ca2+-ATPase
Pulmonary arterial hypertension (PAH)； Pulmonary hypertension due to left heart
disease； Pulmonary hypertension due to lung diseases and hypoxemia； Chronic thromboembolic pulmonary hypertension; PH with unclear or multifactorial mechanisms
Role of bone morphogenetic protein receptor type II (BMP-R2) gene mutations
BMP-R2 突变或功能障碍
Bcl－2
Decreased KV channel activity leads to inhibition of apoptotic volume decrease and apoptosis
number of channels (N) the unitary current amplitude of each channel (iK(V)) the probability that the channels are in the open state (Popen)
NADPH oxidase
resistance caused by vasoconstriction, vascular
cell proliferation and obliteration of pulmonary
microvasculature. These processes lead to right
heart failure.
5-HTT gene polymorphism in patientassium Channels Inhibition of the voltage regulated (Kv) potassium channel by hypoxia or drugs can produce vasoconstriction and has been described in pulmonary artery smooth muscle cells harvested from patients with PPH.
pulmonary hypertension warrant right heart catheterization for confirmation of the hemodynamic findings.
(2008)
Updated Classification of
Pulmonary Hypertension(2009)