Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase‐Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice

Abstract

Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.

Investigating the Vascular Toxicity Outcomes of the Irreversible Proteasome Inhibitor Carfilzomib

“…Even though carfilzomib did not lead to a shift in cellular bioenergetics, it led to a decrease in ATP production via oxidative phosphorylation. Carfilzomib is known to induce a mitochondrial deficit in resistant MM cells in vitro in a mitochondria-derived activator of caspase (SMAC)-Survivin dependent manner leading to increased apoptosis, mitochondrial-derived ROS release and inhibition of mitochondrial respiration, which is in line with our data [ 48 , 49 ]. It should be stressed at this point that the metabolic switch induced by metformin might be of great clinical importance, as drugs that can modulate cellular bioenergetics in a similar manner, are being successfully incorporated in the management of heart failure [ 50 ].…”

“…Sections were hematoxylin–eosin and Sirius red stained for histology, as well as for wall thickness and collagen deposition assessment [ 57 ]. For immunofluorescence (IF) experiments aortic sections were snap-frozen in the optimal cutting temperature (OCT) medium (Tissue-Tek ® O.C.T.™ Compound, Fisher Scientific) and sliced in 3 μm cryosections [ 48 ].…”

“…At least three individual images were acquired and fluorescence intensity of each probe was quantified by using FIJI/image J. For illustration purpose images were reconstructed in to 3D by using Imaris software [ 48 ].…”

Effects of the (Pro)renin Receptor on Cardiac Remodeling and Function in a Rat Alcoholic Cardiomyopathy Model via the PRR-ERK1/2-NOX4 Pathway

“…NOX–derived reactive oxygen species take part in many kinds of cardiovascular diseases. It has been reported that NADPH oxidase-derived superoxide is present in repetitive pulmonary embolism which leads to pulmonary arterial hypertension [45]. Kuroda et al reported that the NOX4-ROS pathway had been shown to aggravate profibrotic responses, remodeling processes, and worsening cardiac function in the failing heart [46].…”

Diabetes mellitus and thrombotic complications

“…Развитие ЛАГ ассоциировано с ремоделированием легочных артерий и нарушением барьерной функции эндотелия. В результате увеличивается продукция провоспалительных цитокинов (фактор некроза опухоли α, интерлейкин 6), что увеличивает экспрессию и активность NADPH-оксидазы и вызывает оксидативный стресс [10].…”