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Journal of the American Heart... Apr 2024
Topics: Humans; Prognosis; Heart Ventricles; Hypertension, Pulmonary; Ventricular Function, Right; Patients
PubMed: 38567674
DOI: 10.1161/JAHA.124.034711 -
The European Respiratory Journal Sep 2023
Topics: Humans; Heart Ventricles; Pulmonary Arterial Hypertension; Heart; Familial Primary Pulmonary Hypertension; Hemodynamics
PubMed: 37696566
DOI: 10.1183/13993003.01513-2023 -
International Journal of Molecular... Jun 2024NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and the maintenance of smooth muscle cells in an undifferentiated state.... (Review)
Review
NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and the maintenance of smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (World Health Organization Group 1 idiopathic disease: PAH) is a fatal disease characterized clinically by elevated pulmonary vascular resistance caused by extensive vascular smooth muscle cell proliferation, perivascular inflammation, and asymmetric neointimal hyperplasia in precapillary pulmonary arteries. In this review, a detailed overview of the specific role of NOTCH3 signaling in PAH, including its mechanisms of activation by a select ligand, downstream signaling effectors, and physiologic effects within the pulmonary vascular tree, is provided. Animal models showing the importance of the NOTCH3 pathway in clinical PAH will be discussed. New drugs and biologics that inhibit NOTCH3 signaling and reverse this deadly disease are highlighted.
Topics: Humans; Receptor, Notch3; Animals; Signal Transduction; Pulmonary Arterial Hypertension; Pulmonary Artery; Hypertension, Pulmonary; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle
PubMed: 38892440
DOI: 10.3390/ijms25116248 -
JCI Insight Sep 2023Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of...
Pulmonary hypertension (PH) is a life-threatening disease characterized by a progressive narrowing of pulmonary arterioles. Although VEGF is highly expressed in lung of patients with PH and in animal PH models, the involvement of angiogenesis remains elusive. To clarify the pathophysiological function of angiogenesis in PH, we compared the angiogenic response in hypoxia (Hx) and SU5416 (a VEGFR2 inhibitor) plus Hx (SuHx) mouse PH models using 3D imaging. The 3D imaging analysis revealed an angiogenic response in the lung of the Hx-PH, but not of the severer SuHx-PH model. Selective VEGFR2 inhibition with cabozantinib plus Hx in mice also suppressed angiogenic response and exacerbated Hx-PH to the same extent as SuHx. Expression of endothelial proliferator-activated receptor γ coactivator 1α (PGC-1α) increased along with angiogenesis in lung of Hx-PH but not SuHx mice. In pulmonary endothelial cell-specific Ppargc1a-KO mice, the Hx-induced angiogenesis was suppressed, and PH was exacerbated along with increased oxidative stress, cellular senescence, and DNA damage. By contrast, treatment with baicalin, a flavonoid enhancing PGC-1α activity in endothelial cells, ameliorated Hx-PH with increased Vegfa expression and angiogenesis. Pulmonary endothelial PGC-1α-mediated angiogenesis is essential for adaptive responses to Hx and might represent a potential therapeutic target for PH.
Topics: Animals; Mice; Cellular Senescence; Disease Models, Animal; DNA Damage; Endothelial Cells; Hypertension, Pulmonary; Hypoxia
PubMed: 37681410
DOI: 10.1172/jci.insight.162632 -
Methodist DeBakey Cardiovascular Journal 2024Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by elevated pulmonary artery pressure and increased pulmonary vascular resistance.... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by elevated pulmonary artery pressure and increased pulmonary vascular resistance. Females have a higher incidence of PAH, which is reflected globally across registries in the United States, Europe, and Asia. However, despite female predominance, women had better outcomes compared with male patients, a finding that has been labeled the "estrogen paradox." Special considerations should be given to women with PAH regarding sexual health, contraception, family planning, and treatment before, during, and after pregnancy. Pregnant women with PAH should be referred to a pulmonary hypertension care center; a multidisciplinary team approach is recommended, and Cesarean section is the preferred mode of delivery. While pregnancy outcomes have improved over the years with PAH-specific therapy, pregnancy portends a high-risk for those with PAH. Continued research is needed to tailor PAH treatment for women.
Topics: Female; Pregnancy; Humans; Male; Hypertension, Pulmonary; Cesarean Section; Pregnancy Outcome; Familial Primary Pulmonary Hypertension; Hypertension
PubMed: 38495664
DOI: 10.14797/mdcvj.1308 -
International Journal of Molecular... Jan 2024Pulmonary hypertension (PH) is recognized as a pathophysiological disorder encompassing a wide spectrum of clinical conditions related to various cardiovascular and...
Pulmonary hypertension (PH) is recognized as a pathophysiological disorder encompassing a wide spectrum of clinical conditions related to various cardiovascular and respiratory diseases [...].
Topics: Humans; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary
PubMed: 38256236
DOI: 10.3390/ijms25021166 -
Current Opinion in Pulmonary Medicine Sep 2023The purpose of this review is to provide an overview of assessment of right ventricular function in the context of pulmonary hypertension and pulmonary arterial... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide an overview of assessment of right ventricular function in the context of pulmonary hypertension and pulmonary arterial hypertension (PAH). We will review unique features of right ventricular anatomy, delineation of cause of pulmonary hypertension through careful right ventricular assessment, echocardiographic and hemodynamic evaluation, and the importance of this assessment in prognosis.
RECENT FINDINGS
The importance of performance in prognosis and risk assessment in patients with pulmonary hypertension has been continually emphasized in ongoing research. Representative parameters of right ventricular function have been shown to be predictive of prognosis in patients with pulmonary hypertension. Further, the importance of serial right ventricular assessment in risk assessment and prognosis has remained an emerging theme.
SUMMARY
Careful evaluation of right ventricular function is paramount in assessing the cause of pulmonary hypertension and severity of disease. Further, it has prognostic significance, as many representative parameters of right ventricular function have been linked with mortality. In our opinion, right ventricular function should be assessed serially throughout the course of treatment in pulmonary hypertension, and baseline parameters in addition to dynamic changes should be incorporated into risk assessment. Achieving normal or near-normal right ventricular performance may serve as a principal goal in the treatment of pulmonary hypertension.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Prognosis; Familial Primary Pulmonary Hypertension; Echocardiography; Ventricular Dysfunction, Right
PubMed: 37410491
DOI: 10.1097/MCP.0000000000000980 -
Respiratory Research Aug 2023Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well...
BACKGROUND
Pulmonary hypertension (PH) is a lethal vascular disease with limited therapeutic options. The mechanistic connections between alveolar hypoxia and PH are not well understood. The aim of this study was to investigate the role of mitotic regulator Polo-like kinase 1 (PLK1) in PH development.
METHODS
Mouse lungs along with human pulmonary arterial smooth muscle cells and endothelial cells were used to investigate the effects of hypoxia on PLK1. Hypoxia- or Sugen5416/hypoxia was applied to induce PH in mice. Plk1 heterozygous knockout mice and PLK1 inhibitors (BI 2536 and BI 6727)-treated mice were checked for the significance of PLK1 in the development of PH.
RESULTS
Hypoxia stimulated PLK1 expression through induction of HIF1α and RELA. Mice with heterozygous deletion of Plk1 were partially resistant to hypoxia-induced PH. PLK1 inhibitors ameliorated PH in mice.
CONCLUSIONS
Augmented PLK1 is essential for the development of PH and is a druggable target for PH.
Topics: Humans; Animals; Mice; Hypertension, Pulmonary; Endothelial Cells; Cell Cycle Proteins; Hypoxia; Mice, Knockout; Polo-Like Kinase 1
PubMed: 37598171
DOI: 10.1186/s12931-023-02498-z -
American Journal of Respiratory and... Aug 2023
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Circulation
PubMed: 37348119
DOI: 10.1164/rccm.202306-0990ED -
Cardiovascular Research Oct 2023Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH... (Review)
Review
Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.
Topics: Female; Male; Humans; Pulmonary Arterial Hypertension; Transforming Growth Factor beta; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary; Signal Transduction; Bone Morphogenetic Protein Receptors, Type II
PubMed: 37595264
DOI: 10.1093/cvr/cvad129