Pulmonary Hypertension: Pathophysiology and Signaling Pathways

Maron, Bradley A.; Loscalzo, Joseph

doi:10.1007/978-3-642-38664-0_2

Cited by 28 publications

(21 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this context, the binding of Ang II to Ang II receptor 1 (AT 1 R) induces vasoconstriction, while binding to AT 2 R triggers vasodilation . Thus, elevated levels of renin, angiotensin‐converting enzyme (ACE), Ang II, and AT 1 R have been observed in experimental models as well as in patients with pulmonary hypertension (PH) .…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and noncurative treatments. As mice deficient in P‐selectin glycoprotein ligand 1 (PSGL‐1) develop a spontaneous SSc‐like syndrome, we undertook this study to analyze whether they develop PAH and to examine the molecular mechanisms involved. Methods Doppler echocardiography was used to estimate pulmonary pressure, immunohistochemistry was used to assess vascular remodeling, and myography of dissected pulmonary artery rings was used to analyze vascular reactivity. Angiotensin II (Ang II) levels were quantified by enzyme‐linked immunosorbent assay, and Western blotting was used to measure Ang II type 1 receptor (AT1R), AT2R, endothelial cell nitric oxide synthase (eNOS), and phosphorylated eNOS expression in lung lysates. Flow cytometry allowed us to determine cytokine production by immune cells and NO production by endothelial cells. In all cases, there were 4–8 mice per experimental group. Results PSGL‐1−/− mice showed lung vessel wall remodeling and a reduced mean ± SD expression of pulmonary AT2R (expression ratio [relative to β‐actin] in female mice age >18 months: wild‐type mice 0.799 ± 0.508 versus knockout mice 0.346 ± 0.229). With aging, female PSGL‐1−/− mice had impaired up‐regulation of estrogen receptor α (ERα) and developed lung vascular endothelial dysfunction coinciding with an increase in mean ± SEM pulmonary Ang II levels (wild‐type 48.70 ± 5.13 pg/gm lung tissue versus knockout 78.02 ± 28.09 pg/gm lung tissue) and a decrease in eNOS phosphorylation, leading to reduced endothelial NO production. These events led to a reduction in the pulmonary artery acceleration time:ejection time ratio in 33% of aged female PSGL‐1−/− mice, indicating pulmonary hypertension. Importantly, we found expanded populations of interferon‐γ–producing PSGL‐1−/− T cells and B cells and a reduced presence of regulatory T cells. Conclusion The absence of PSGL‐1 induces a reduction in Treg cells, NO production, and ERα expression and causes an increase in Ang II in the lungs of female mice, favoring the development of PAH.

show abstract

Section: Introductionmentioning

confidence: 99%

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Rafael

Fuente-Fernández

Morales‐Cano

et al. 2020

Arthritis & Rheumatology

View full text Add to dashboard Cite

show abstract

“…Rarely, patients with PH that occurs due to interplay between molecular and genetic factors in the absence of other comorbidities are reclassified as having pulmonary arterial hypertension (PAH) 62 . In clinical practice, however, overlap between pulmonary hypertension sub-groups is common, which may confound diagnosis and treatment decision-making 63 , 64 . Therefore, there is an increasing emphasis on studying the molecular basis of pulmonary hypertension in order to delineate pulmonary vascular from other forms of cardiopulmonary diseases 65 , 66 , as well as to predict treatment-responsiveness clinically 67 .…”

Section: Systems Biology In Cardiovascular Medicinementioning

confidence: 99%

“…Hydrolysis of cGMP to inactive 5’-GMP by phosphodiesterase type-V (PDE-V) is an endogenous counter-regulatory mechanism controlling NO bioactivity. However, diminished NO bioavailability and impaired NO-sGC signaling due, in part, to increased pulmonary vascular oxidant stress 68 are associated with endothelial dysfunction, increased vascular smooth muscle cell proliferation, thrombosis, and vascular fibrosis that contribute to adverse vascular remodeling and pulmonary hypertension in PAH 63 . Although PDE-V inhibition and other novel direct NO delivery systems 69 provide benefit to PAH patients 70 , the optimal strategy for inducing maximal NO bioactivity is not established.…”

Section: Systems Biology In Cardiovascular Medicinementioning

confidence: 99%

Systems biology: An emerging strategy for discovering novel pathogenetic mechanisms that promote cardiovascular disease

Maron

Leopold

2016

gcsp

View full text Add to dashboard Cite

Reductionist theory proposes that analyzing complex systems according to their most fundamental components is required for problem resolution, and has served as the cornerstone of scientific methodology for more than four centuries. However, technological gains in the current scientific era now allow for the generation of large datasets that profile the proteomic, genomic, and metabolomic signatures of biological systems across a range of conditions. The accessibility of data on such a vast scale has, in turn, highlighted the limitations of reductionism, which is not conducive to analyses that consider multiple and contemporaneous interactions between intermediates within a pathway or across constructs. Systems biology has emerged as an alternative approach to analyze complex biological systems. This methodology is based on the generation of scale-free networks and, thus, provides a quantitative assessment of relationships between multiple intermediates, such as protein-protein interactions, within and between pathways of interest. In this way, systems biology is well positioned to identify novel targets implicated in the pathogenesis or treatment of diseases. In this review, the historical root and fundamental basis of systems biology, as well as the potential applications of this methodology are discussed with particular emphasis on integration of these concepts to further understanding of cardiovascular disorders such as coronary artery disease and pulmonary hypertension.

show abstract

“…Pulmonary hypertension (PH) is predominantly defined by a mean pulmonary artery pressure at rest greater than or equal to 25 mm Hg. It is an enigmatic vascular disease and the pathogenesis of PH is multifactorial of origin and, hence, is categorized as idiopathic type [ 1 – 4 ]. As PH develops in a wide variety of clinical circumstances and is associated with diverse histological manifestations, a classification system is developed [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of miRNAs in Pulmonary Hypertension

Gupta¹,

2015

International Journal of Hypertension

View full text Add to dashboard Cite

MicroRNAs (miRNAs) have emerged as a new class of posttranscriptional regulators of many cardiac and vascular diseases. They are a class of small, noncoding RNAs that contributes crucial roles typically through binding of the 3′-untranslated region of mRNA. A single miRNA may influence several signaling pathways associated with cardiac remodeling by targeting multiple genes. Pulmonary hypertension (PH) is a rare disorder characterized by progressive obliteration of pulmonary (micro) vasculature that results in elevated vascular resistance, leading to right ventricular hypertrophy (RVH) and RV failure. The pathology of PH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) proliferation. There is no cure for this disease. Thus, novel intervention pathways that govern PH induced RVH may result in new treatment modalities. Current therapies are limited to reverse the vascular remodeling. Recent studies have demonstrated the roles of various miRNAs in the pathogenesis of PH and pulmonary disorders. This review provides an overview of recent discoveries on the role of miRNAs in the pathogenesis of PH and discusses the potential for miRNAs as therapeutic targets and biomarkers of PH at clinical setting.

show abstract

Pulmonary Hypertension: Pathophysiology and Signaling Pathways

Cited by 28 publications

References 125 publications

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Spontaneous Pulmonary Hypertension Associated With Systemic Sclerosis in P‐Selectin Glycoprotein Ligand 1–Deficient Mice

Systems biology: An emerging strategy for discovering novel pathogenetic mechanisms that promote cardiovascular disease

Modulation of miRNAs in Pulmonary Hypertension

Contact Info

Product

Resources

About