scholarly journals Modulation of miRNAs in Pulmonary Hypertension

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Diseases ◽  
Treatment Modalities ◽  
Small Noncoding Rnas ◽  
New Class ◽  
Cell Remodeling ◽  
Arterial Endothelial Cell ◽  
Current Therapies ◽  
Pulmonary Arterial ◽  
New Treatment

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.

scholarly journals Infection in pulmonary vascular diseases: Would another consortium really be the way to go?

2019 ◽  
Vol 2019 (1) ◽  
Author(s):  
Ghazwan Butrous ◽  
Alistair Mathie
Keyword(s):  
Pulmonary Hypertension ◽  
Targeted Therapies ◽  
Vascular Diseases ◽  
Developed Countries ◽  
Medical Community ◽  
Class Iii ◽  
Left Heart Failure ◽  
Therapeutic Modalities ◽  
Pulmonary Arterial ◽  
The Developed Countries

[first paragraph of article]There has been a clear engagement by the medical community with pulmonary hypertension after the approval of targeted therapies and the introduction of more therapeutic modalities in the last 18 years. The increasing number of scientific sessions and conferences was inevitable. Major initial interest was from the developed countries, which concentrated on prevalent etiologies: primary (later called idiopathic) pulmonary arterial hyposecretion and secondary to connective tissue disorders currently both classified as Class I. Unfortunately, a lesser consideration was given to other causes of pulmonary hypertension such as secondary to left heart failure (Class II) or hypoxic pulmonary disease (Class III). This is presumably due to both the complexity and the multifactorial etiologies of these causes and the lack of availability of targeted therapies. 

The endothelin system in pulmonary hypertension

2003 ◽  
Vol 81 (6) ◽  
pp. 542-554 ◽  
Author(s):  
René P Michel ◽  
David Langleben ◽  
Jocelyn Dupuis
Keyword(s):  
Clinical Trials ◽  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Tissue Expression ◽  
Vascular Endothelial ◽  
Receptor Antagonists ◽  
New Class ◽  
Endothelin System ◽  
Pulmonary Arterial ◽  
Medial Hypertrophy

Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstric tive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA–ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.Key words: pulmonary circulation, pulmonary pathology, receptor, preclinical studies, clinical studies, antagonist.

Abstract 1637: Difference of Pulmonary Arterial Microvasculature in Patients with Pulmonary Hypertension Using Scanning Electron Microscope

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Aya Miura ◽  
Kazufumi Nakamura ◽  
Kengo F Kusano ◽  
Hiromi Matsubara ◽  
Daiji Miura ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Electron Microscope ◽  
Scanning Electron Microscope ◽  
Structural Characteristics ◽  
Vascular Diseases ◽  
Pulmonary Capillary ◽  
Pulmonary Arterial ◽  
Morphological Differences ◽  
Underlying Diseases ◽  
Scanning Electron

Background and Objectives: Pulmonary vascular diseases (pulmonary arterial hypertension: PAH, pulmonary veno-occlusive disease: PVOD and pulmonary capillary hemangiomatosis: PCH) are well-known diseases that cause pulmonary hypertension (PH). However, the differences of structural characteristics of pulmonary microvasculature in these diseases have not been elucidated enough. We examined the morphological differences among these diseases by methacrylate resin (Mercox) perfusion using scanning electron microscope. Methods and Results: Ten lung samples were 8 patients with PH and 2 control subjects without PH. These were obtained at lung transplantations or autopsies. Microvascular corrosion replicas were made by Mercox perfusion from the pulmonary artery. Pathological diagnosis revealed 5 PAH, 2 PVOD and 1 PCH in patients with PH. In PAH samples, small arteries or arterioles showed twisted and tortuous courses, but such vessels were not observed in samples from control, PVOD and PCH. Binary branching was observed in control, but not in PVOD and PCH. In PVOD and PCH, several branching was commonly observed. Moreover, the loss of capillary network and the disruption of arterioles were more severe in samples from PVOD and PCH patients than in samples from PAH patients. Conclusion: Pulmonary microvascular morphology is seriously different among the type of underlying diseases in PH patients.

Promises and Dangers of Combination Therapy

2017 ◽  
Vol 35 (1-2) ◽  
pp. 56-60 ◽  
Author(s):  
Wolfgang Kruis ◽  
Phuong G. Nguyen ◽  
Julia Morgenstern
Keyword(s):  
Combination Therapy ◽  
Infectious Complications ◽  
Treatment Modalities ◽  
Therapeutic Effects ◽  
Aminosalicylic Acid ◽  
Number Of Patients ◽  
Tnf Α ◽  
Serious Infections ◽  
Current Therapies ◽  
New Treatment

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies.

scholarly journals H2S inhibits pulmonary arterial endothelial cell inflammation in rats with monocrotaline-induced pulmonary hypertension

2016 ◽  
Vol 97 (3) ◽  
pp. 268-278 ◽  
Author(s):  
Shasha Feng ◽  
Siyao Chen ◽  
Wen Yu ◽  
Da Zhang ◽  
Chunyu Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Endothelial Cell ◽  
Pulmonary Arterial

scholarly journals Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell–Dependent Endothelial Cell Apoptosis

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 985-996 ◽  
Author(s):  
Grégoire Ruffenach ◽  
Ellen O’Connor ◽  
Mylène Vaillancourt ◽  
Jason Hong ◽  
Nancy Cao ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
T Cell ◽  
Cell Apoptosis ◽  
Oxidized Lipids ◽  
Endothelial Cell Apoptosis ◽  
Arterial Endothelial Cell ◽  
Pulmonary Arterial ◽  
Cluster Of Differentiation ◽  
Cells Cultured

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell–mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE–fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE–fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE–induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell–dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

Abstract 600: Activation of p53 in Pulmonary Arterial Endothelial Cells with Dysfunctional BMPR2 Rescues DNA Damage, Apoptosis and Persistent Pulmonary Hypertension

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jan K Hennigs ◽  
Caiyun Grace Li ◽  
Kazuya Miyagawa ◽  
Matthew Roughley ◽  
Matthew V Elliott ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pulmonary Hypertension ◽  
Target Genes ◽  
Vascular Diseases ◽  
Angiogenic Factor ◽  
Persistent Pulmonary Hypertension ◽  
Small Molecule Compound ◽  
Life Threatening ◽  
A Cell ◽  
Pulmonary Arterial

Pulmonary arterial (PA) hypertension (PAH) is a life-threatening disease characterized by loss of microvessels, the result of endothelial cell (EC) apoptosis associated with dysfunction or a mutation in BMPR2. We identified p53 as critical in the formation of a DNA damage-inducible transcriptionally active complex with PPARγ, an important downstream factor of BMPR2 signaling. The p53-PPARγ complex regulates genes promoting PAEC homeostasis. Upon reoxygenation after hypoxia, PAEC with defective BMPR2 fail to stabilize p53 leading to mitochondrial dysfunction, DNA damage, endothelial apoptosis and persistent pulmonary hypertension (PH) in mice. We therefore hypothesized that in PAEC, pharmacological activation of p53 by the small molecule compound Nutlin-3 would stabilize the PPARγ-p53 complex downstream of BMPR2 to reverse the PH phenotype. Indeed, we showed that in PAEC transfected with BMPR2 siRNA, disruption of the PPARγ-p53 complex upon reoxygenation was prevented by Nutlin-3 treatment. This was associated with a reduction in DNA damage as assessed by Histone 2AX phosphorylation. In PAEC isolated from PAH patients with a BMPR2 mutation, Nutlin-3 treatment induced repair of prevalent DNA damage as determined by the Comet assay, and improved PAEC survival as measured by Caspase 3/7 activity. In PAEC with a BMPR2 mutation, Nutlin treatment stabilized p53, and induced PPARγ-p53 complex formation and expression of target genes, i.e., apelin (a pro-angiogenic factor), GADD45A (a DNA repair enzyme) and p21 (a cell cycle inhibitor) as detected by quantitative PCR and western immunoblots. In EC-specific BMPR2 knockout mice, we have observed persistent chronic hypoxia induced PH even after a month of reoxygenation in room air. We now show that this can be reversed by daily i.p. treatment with Nutlin-3a (12 mg/kg) during reoxygenation. In conclusion, pharmacological stabilization of p53 by Nutlin-3 in PAEC with dysfunctional BMPR2 induces repair of DNA damage, improves PAEC survival and rescues persistent pulmonary hypertension. These results auger well for pursuing the use of Nutlin-3 in pulmonary hypertension and other vascular diseases associated with DNA damage such as atherosclerosis.

Management of thoracic aortic lesions - the future is endovascular

VASA ◽  
2012 ◽  
Vol 41 (3) ◽  
pp. 163-176 ◽  
Author(s):  
Weidenhagen ◽  
Bombien ◽  
Meimarakis ◽  
Geisler ◽  
A. Koeppel
Keyword(s):  
Thoracic Aorta ◽  
Clinical Decision Making ◽  
Treatment Options ◽  
Clinical Decision ◽  
Clinical Results ◽  
Treatment Modalities ◽  
Traumatic Rupture ◽  
Descending Thoracic Aorta ◽  
New Treatment ◽  
Aneurysm Dissection

Open surgical repair of lesions of the descending thoracic aorta, such as aneurysm, dissection and traumatic rupture, has been the “state-of-the-art” treatment for many decades. However, in specialized cardiovascular centers, thoracic endovascular aortic repair and hybrid aortic procedures have been implemented as novel treatment options. The current clinical results show that these procedures can be performed with low morbidity and mortality rates. However, due to a lack of randomized trials, the level of reliability of these new treatment modalities remains a matter of discussion. Clinical decision-making is generally based on the experience of the vascular center as well as on individual factors, such as life expectancy, comorbidity, aneurysm aetiology, aortic diameter and morphology. This article will review and discuss recent publications of open surgical, hybrid thoracic aortic (in case of aortic arch involvement) and endovascular repair in complex pathologies of the descending thoracic aorta.

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