Mechanisms of pulmonary hypertension in chronic obstructive pulmonary disease: A pathophysiologic review

Wrobel, Jérémy; Thompson, Bruce; Williams, Trevor

doi:10.1016/j.healun.2012.02.029

Cited by 86 publications

(82 citation statements)

References 87 publications

(91 reference statements)

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“…[30][31][32] Cor pulmonale characterized by right ventricular hypertrophy and dilatation is also commonly secondary to PH caused by respiratory disorders. 33 It is known that hypoxia, inflammation and other elements have important roles in the development of PH.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

Yue

Guan

Wang

et al. 2013

Laboratory Investigation

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Hypoxia-induced pulmonary hypertension (PH), which is characterized by vasoconstriction and subsequent structural remodeling of blood vessels, is an important event in chronic obstructive pulmonary disease patients and in people living at high altitudes. Hypoxia-inducible factor-1a (HIF-1a) and its regulator four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1) have important roles in hypoxia-induced PH. is critical for myogenesis and related diseases; however, the role of miR-206 in hypoxia-induced PH is unknown. miR-206 expression was evaluated in a hypoxic rat model and in cultured hypoxic pulmonary artery smooth muscle cells (PASMCs) using real-time quantitative PCR (RT-qPCR). HIF-1a and Fhl-1 expression were evaluated using RT-qPCR, western blotting, immunohistochemistry and immunofluorescence. The function of miR-206 was assessed by transfecting miR-206 mimics and inhibitors. Dualluciferase reporter gene assays and western blotting were performed to validate the target genes of miR-206. siRNA targeted against Fhl-1 was used to investigate the effect of Fhl-1 on miR-206. Flow cytometry was used to detect the cell cycle phase distribution in each group of PASMCs. Significant downregulation of miR-206 in hypoxic lung tissue and PASMCs was identified, whereas HIF-1a and Fhl-1 were upregulated in these samples. The expression of miR-206 in the serum was different from that in the lung tissue. Transfection of pre-miR miR-206 in hypoxic conditions led to increased expression of HIF-1a and Fhl-1 rather than abolishing hypoxia-induced HIF-1a and Fhl-1, as was expected, and promoted the entry of cells into the S phase and enhanced PASMC proliferation. Fhl-1-targeted siRNA in PASMC prevented cell proliferation and led to an increased proportion of cells in the G1 phase without altering miR-206 expression. Bioinformatic analysis and dual-luciferase reporter gene assays revealed direct evidence for miR-206 targeting of HIF-1a. In conclusion, hypoxia-induced downregulation of miR-206 promotes PH by targeting the HIF-1a/Fhl-1 pathway in PASMCs. miR-206 could be a triggering factor of early stage of hypoxia-induced PH. Hypoxia-induced pulmonary hypertension (PH) is a serious disorder characterized by pulmonary vasoconstriction and enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) that lead to structural remodeling of blood vessel walls. PH is a common clinical manifestation of chronic obstructive pulmonary disease (COPD) and in people who live at high altitude. 1 Hypoxia-inducible factor-1a (HIF-1a) has a key role in the pathophysiology of hypoxia-induced PH.The four-and-a-half LIM domain 1 (Fhl-1) protein, a member of the Fhl family, has also been implicated in the biological pathways of muscle growth and differentiation in PH 2-4 and is regulated by HIF-1a in a feedback loop that serves to limit HIF-1a activity under conditions of prolonged hypoxia. 5 MicroRNAs (miRs) are a class of B23-nucleotide, noncoding single-stranded RNAs that regulate gene function by identifying the 3 0 -untransl...

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Section: Discussionmentioning

confidence: 99%

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

Yue

Guan

Wang

et al. 2013

Laboratory Investigation

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“…[5][6][7][8][9][10][11] This has led to a renewed interest in the underlying pathogenesis of PH in COPD as a basis for determining the appropriateness of pursuing PH-specific therapies. 12 The pathogenesis of COPD-associated PH is complex. 12 Although hypoxia plays a key role, other factors, such as pulmonary arterial remodeling, have been implicated.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Arterial Remodeling in Chronic Obstructive Pulmonary Disease is Lobe Dependent

et al. 2013

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Pulmonary arterial remodeling has been demonstrated in patients with severe chronic obstructive pulmonary disease (COPD), but it is not known whether lobar heterogeneity of remodeling occurs. Furthermore, the relationship between pulmonary hypertension (PH) and pulmonary arterial remodeling in COPD has not been established. Muscular pulmonary arterial remodeling in arteries 0.10-0.25 mm in diameter was assessed in COPD-explanted lungs and autopsy controls. Remodeling was quantified as the percentage wall thickness to vessel diameter (%WT) using digital image analysis. Repeat measures mixed-effects remodeling for %WT was performed according to lobar origin (upper and lower), muscular pulmonary arterial size (small, medium, and large), and echocardiography-based pulmonary arterial pressure (no PH, mild PH, and moderate-tosevere PH). Lobar perfusion and emphysema indices were determined from ventilationperfusion and computed tomography scans, respectively. Overall, %WT was greater in 42 subjects with COPD than in 5 control subjects (P < 0:0001 ). Within the COPD group, %WT was greater in the upper lobes (P < 0:0001 ) and in the small muscular pulmonary arteries (P < 0:0001 ). Lobar differences were most pronounced in medium and large arteries. Lobar emphysema index was not associated with arterial remodeling. However, there was a significant positive relationship between the lobar perfusion index and pulmonary arterial remodeling (P ¼ 0:024). The presence of PH on echocardiography showed only a trend to a small effect on lower lobe remodeling. The pattern of pulmonary arterial remodeling in COPD is complicated and lobe dependent. Differences in regional blood flow partially account for the lobar heterogeneity of pulmonary arterial remodeling in COPD.

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“…Mild-to-moderate PHT was common in severe COPD cases, whereas severe PHT was rare [13,20]. Thabut et al reported a mean PAP>25 mmHg in 50% of COPD patients who were scheduled for lung transplantation or lung volume reduction surgery.…”

Section: Epidemiologymentioning

confidence: 99%

“…This leads to the onset of pulmonary vasoconstriction and vascular remodeling. Vascular remodeling also [20].…”

Section: Pulmonary Vascular Remodelingmentioning

confidence: 99%

Pulmonary Hypertension in Patients with Chronic Obstructive Pulmonary Disease: A Review for Definition, Epidemiology, Pathology, and Diagnosis

Gülmez¹

2017

Gen Med

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Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by progressive and persistent restriction of airflow with a prevalence of 19-25%. The main symptoms are shortness of breath, cough, and sputum production. Smoking is the most common cause and quitting smoking is the only action which prevents developing and progressing of COPD.Pulmonary hypertension (PHT) which is defined as a mean pulmonary artery pressure of ≥ 25 mmHg measured by right heart catheterization at rest is a common complication of COPD and it has been investigated under the title of "Class III: Pulmonary Hypertension due to Pulmonary Disease and/or Hypoxia" according to the updated clinical classification in the 5 th World Pulmonary Hypertension Symposium. Although pathogenesis is complex, it often involves HPV and pulmonary vascular remodeling. In this review, the PHT which mainly develops secondary to COPD is discussed.

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Mechanisms of pulmonary hypertension in chronic obstructive pulmonary disease: A pathophysiologic review

Cited by 86 publications

References 87 publications

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

MicroRNA-206 is involved in hypoxia-induced pulmonary hypertension through targeting of the HIF-1α/Fhl-1 pathway

Pulmonary Arterial Remodeling in Chronic Obstructive Pulmonary Disease is Lobe Dependent

Pulmonary Hypertension in Patients with Chronic Obstructive Pulmonary Disease: A Review for Definition, Epidemiology, Pathology, and Diagnosis

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