Pathobiology of pulmonary arterial hypertension and right ventricular failure

Voelkel, Norbert F.; Gomez-Arroyo, José; Abbate, Antonio; Bogaard, Harm Jan; Nicolls, Mark R.

doi:10.1183/09031936.00046612

Cited by 238 publications

(229 citation statements)

References 107 publications

(120 reference statements)

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“…1 Resident lung vascular cells, inflammatory cells and cells of the immune system, bone marrow-derived cells, and various precursor or stem cells are all potential participants in the sequence of events leading to vascular remodeling; their particular and interactive roles in pulmonary vascular remodeling are under active investigation in a number of experimental models of PAH. [2][3][4][5][6] The concepts of apoptosis resistance of proliferating vascular cells 1,7 and of misguided angiogenesis have now advanced the field, and we have proposed that angioobliterative PAH is initiated by pulmonary vascular endothelial cell apoptosis. However, by itself endothelial cell apoptosis is insufficient to cause severe PAH.…”

Section: Introductionmentioning

confidence: 99%

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

et al. 2015

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The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416/ chronic hypoxia (SuHx) rat model. Here we address, at first glance, the confusing and paradoxical aspect of the model, namely, that treatment of rats with the antiangiogenic vascular endothelial growth factor (VEGF) receptor 1 and 2 kinase inhibitor, Sugen 5416, when combined with chronic hypoxia, causes angioproliferative pulmonary vascular disease. We postulated that signaling through the unblocked VEGF receptor VEGFR3 (or flt4) could account for some of the pulmonary arteriolar lumen-occluding cell growth. We also considered that Sugen 5416-induced VEGFR1 and VEGFR2 blockade could alter the expression pattern of VEGF isoform proteins. Indeed, in the lungs of SuHx rats we found increased expression of the ligand proteins VEGF-C and VEGF-D as well as enhanced expression of the VEGFR3 protein. In contrast, in the failing right ventricle of SuHx rats there was a profound decrease in the expression of VEGF-B and VEGF-D in addition to the previously described reduction in VEGF-A expression. MAZ51, an inhibitor of VEGFR3 phosphorylation and VEGFR3 signaling, largely prevented the development of angioobliteration in the SuHx model; however, obliterated vessels did not reopen when animals with established PAH were treated with the VEGFR3 inhibitor. Part of the mechanism of vasoobliteration in the SuHx model occurs via VEGFR3. VEGFR1/VEGFR2 inhibition can be initially antiangiogenic by inducing lung vessel endothelial cell apoptosis; however, it can be subsequently angiogenic via VEGF-C and VEGF-D signaling through VEGFR3.

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Section: Introductionmentioning

confidence: 99%

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

et al. 2015

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“…The endothelial layer acts as a barrier between the serum and downstream vascular components and is a sensor to stimuli such as sheer stress, toxins, and signaling proteins. Exuberant EC proliferation also leads to the development of glomeruloid-like structures located at bifurcation sites of small pulmonary arteries (Jonigk et al, 2011;Voelkel et al, 2012). Commonly termed plexiform lesions, the growth of these characteristic irreversible lesions leads to vascular occlusion (Voelkel et al, 2012) and has been associated with poor prognosis in patients (Rai et al, 2008).…”

Section: Vascular Remodelingmentioning

confidence: 99%

“…A proposed mechanism of vascular remodeling has emerged which describes an initial apoptotic event causing an emergence of apoptosis-resistant, dysfunctional ECs (Sakao et al, 2009;Voelkel et al, 2012). With the dysfunction of ECs, comes an imbalance in production of vasoactive mediators.…”

Section: Vascular Remodelingmentioning

confidence: 99%

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

Drozd¹,

Deng²,

Jiang³

et al. 2014

Canadian Journal of Cardiology

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“…88 Although the roles of class I HDACs in RV cardiomyocytes remain largely uncharacterized, at least part of the mechanism for the beneficial effect of class I HDAC inhibition on the RV appears to be governed via suppression of inflammation. 79 …”

Section: Mechanisms Of Action Of Hdac Inhibitors In Phmentioning

confidence: 99%

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

2015

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Reversible lysine acetylation has emerged as a critical mechanism for controlling the function of nucleosomal histones as well as diverse nonhistone proteins. Acetyl groups are conjugated to lysine residues in proteins by histone acetyltransferases and removed by histone deacetylases (HDACs), which are also commonly referred to as lysine deacetylases. Over the past decade, many studies have shown that HDACs play crucial roles in the control of left ventricular (LV) cardiac remodeling in response to stress. Small molecule HDAC inhibitors block pathological hypertrophy and fibrosis and improve cardiac function in various preclinical models of LV failure. Only recently have HDACs been studied in the context of right ventricular (RV) failure, which commonly occurs in patients who experience pulmonary hypertension (PH). Here, we review recent findings with HDAC inhibitors in models of PH and RV remodeling, propose next steps for this newly uncovered area of research, and highlight potential for isoform-selective HDAC inhibitors for the treatment of PH and RV failure. Heart failure due to systolic and/or diastolic ventricular dysfunction afflicts approximately 6 million Americans, placing an economic burden on the United States that is projected to increase to nearly $100 billion annually by 2030. 1 Most preclinical studies of heart failure focus on the left ventricle (LV) of the heart, because LV failure causes death in the large populations of patients who experience conditions such as ischemic heart disease and resistant systemic hypertension. As such, significantly more is known about the molecular mechanisms governing LV failure than about those associated with right ventricular (RV) failure.In patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary circulation increases pulmonary vascular resistance and often results in RV failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, highlighting an urgent need for novel therapeutics. 2 Current standards-of-care (SOC) for patients with PH involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins. 3 It is hypothesized that more effective therapeutic strategies will be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 4 Importantly, maintenance of RV function is the key determinant of survival in patients with PH, and it is unclear whether SOC therapy for LV failure (e.g., β-blockers and angiotensin-converting enzyme inhibitors) is effective for RV failure. 5 Clearly, increased emphasis needs to be placed on elucidating pathogenic mechanisms in this chamber of the heart.Multiple small molecule inhibitors of histone deacetylase (HDAC) enzymes have been shown...

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Pathobiology of pulmonary arterial hypertension and right ventricular failure

Cited by 238 publications

References 107 publications

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

The Effects of a Novel Endothelin Receptor Antagonist, Macitentan, on Right Ventricular Substrate Utilization and Function in a Sugen5416/Hypoxia Rat Model of Severe Pulmonary Artery Hypertension

Emerging Roles for Histone Deacetylases in Pulmonary Hypertension and Right Ventricular Remodeling (2013 Grover Conference series)

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