Antioxidant treatment attenuates pulmonary arterial hypertension-induced heart failure

Abstract

have been implicated in the development of pathological ventricular hypertrophy and the ensuing contractile dysfunction. Using the rat monocrotaline (MCT) model of pulmonary arterial hypertension (PAH), we recently reported oxidative stress in the failing right ventricle (RV) with no such stress in the left ventricle of the same hearts. We used the antioxidant EUK-134 to assess the role of ROS in the pathological remodeling and dysfunction of the RV. PAH was induced by an injection of MCT (80 mg/kg, day 0), treatment with EUK-134 (25 mg/kg, once every 2 days) of control and MCT-injected animals [congestive heart failure (CHF) group] was started on day 10, and animals were analyzed on day 22. EUK-134 treatment of the CHF group attenuated cardiomyocyte hypertrophy and associated changes in mRNA expression (myosin heavy chain-␤ and deiodinase type 3). It also reduced RV oxidative stress and proapoptotic signaling and prevented interstitial fibrosis. Cardiac MRI showed that ROS scavenging did not affect the 37% increase in end-diastolic volume of the RV in the CHF relative to the control group, but the threefold increase in end-systolic volume was reduced by 42% in the EUK-134-treated CHF group. The improved systolic function was confirmed using echocardiography by an assessment of tricuspid annular plane systolic excursion. These data indicate an important role of ROS in RV cardiomyocyte hypertrophy and contractile dysfunction due to PAH and show the potential of EUK-class antioxidants as complementary therapeutics in the treatment of RV dysfunction in PAH. right ventricle; fibrosis; monocrotaline PULMONARY ARTERIAL HYPERTENSION (PAH) due to increased pulmonary vascular resistance causes pressure overload of the right ventricle (RV), which, in turn, leads to RV hypertrophy. This response is aimed at normalizing wall stress and may be successfully compensatory, but at higher levels of PAH, pathological remodeling of the RV progresses to dilation and failure (27). RV failure is a principal secondary cause of morbidity and mortality in patients suffering from PAH (20), and the degree of RV remodeling is predictive of patient outcome (38).A previous study (9) in animal models of PAH has suggested a role for ROS in pathological RV remodeling. This was corroborated by a recent study (28) of PAH in rats in which we detected increased oxidative stress in cardiomyocytes of the failing RV. In this study, NADPH oxidase and mitochondria were identified as sources of the increase in ROS production. These changes were specific to the overloaded RV, since they were not observed in the left ventricles (LVs) of the same hearts (28). The oxidative stress may at least in part account for the activation of proapoptotic pathways found in the failing RV in PAH (2) but may also account for other aspects of pathological remodeling. An in vitro study (33) has shown that ROS may act as signaling molecules driving cardiomyocyte hypertrophy. A study (34) of LV remodeling has shown that high cellular ROS levels activate matrix remodeling and i...

A View on Imaging in Drug Research and Development for Respiratory Diseases

“…Flow-derived PAP and right ventricular mass and function determined with MRI correlated better with RHC than echocardiography-assessed parameters (Urboniene et al, 2010). In the same model, treatment with antioxidant reduced the 3-fold increase in end-systolic right ventricle volume by 42% (Redout et al, 2010).…”

American Thyroid Association Guide to Investigating Thyroid Hormone Economy and Action in Rodent and Cell Models

“…When the resolution of echocardiography is insufficient to detect effects, MRI provides superior delineation of structures throughout the cardiac cycle with high time resolution (546,547). The same considerations with respect to anesthesia and temperature control apply as for ultrasound analysis.…”

IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells

“…On the other hand, oxidative stress induced by H 2 O 2 increases Dio2 and Dio3 gene transcription and D3 activity in cultured rat astrocytes (30), whereas pretreatment with an antioxidant prevents the increase in Dio3 mRNA levels in rats with pathological ventricular hypertrophy (60), which suggests that oxidative stress is involved in these processes.…”