Cardiac and Vascular Atrogin-1 mRNA Expression is Not Associated with Dexamethasone Efficacy in the Monocrotaline Model of Pulmonary Hypertension

Abstract

Atrophic signaling elements of the ubiquitin-proteasome system (UPS) are involved in skeletal muscle wasting as well as pressure overload models of heart failure. In our prior experiments, we demonstrated a transcriptional down-regulation of atrophy-inducing vascular E3 ubiquitin ligases in a toxic model of pulmonary hypertension where pulmonary artery and right ventricle (RV) hypertrophy are evident. Given the numerous reports of glucocorticoid activation of the UPS and the negative regulator of muscle mass, myostatin, we investigated the efficacy of dexamethasone to reverse monocrotaline (MCT)-induced pulmonary hypertension and augment atrogin-1 expression in both pulmonary arteries and myocardium. Dexamethasone caused significant reductions in body weight in combination with MCT. As predicted, MCT-induced pulmonary hypertension was evident by increases in RV systolic pressure, right ventricle to left ventricle plus septal weight ratios (RV/LVS) and arterial remodeling. MCT treatment significantly reduced both RV and PA atrogin-1 expression. Dexamethasone treatment reversed the MCT-induced pathological indices and restored RV atrogin-1 expression, but did not impact atrogin-1 expression in pulmonary arteries. Myostatin was poorly expressed in pulmonary arteries compared to the RV, and dexamethasone treatment increase RV myostatin in controls but not MCT-treated rats. These findings suggest that mechanisms independent of myostatin/atrogin-1 are responsible for glucocorticoid efficacy in this model of pulmonary hypertension.

Muscle RING Finger-1 Promotes a Maladaptive Phenotype in Chronic Hypoxia-Induced Right Ventricular Remodeling

“…Because we did not see clear differences in RVSP or HCT that would drive the pattern of RV/LVS phenotypes, we believe it is unlikely that a substantial load-dependent differential was incurred by the genetic manipulations in this study. MuRF1, unlike its relative ubiquitin ligase Atrogin-1 (paffet, that uterus study) [21] [33] , does not appear to have an important role in smooth muscle regulation. Alternatively, one might consider a role for MuRF1 in response to hypoxia globally.…”

“…While off-target pleiotropic effects of resveratrol cannot be discounted, these findings motivated further inquiry into the role of ubiquitin ligases in aspects of PAH. Subsequent studies of MCT found atrogin-1 to be downregulated in the right ventricle, as well [21] . Interestingly, MuRF1 is not highly expressed in smooth muscle cells, despite its prominent role in skeletal and cardiac muscle growth.…”

“…qPCR was conducted as previously described [20] [21] using a Roche 480 LightCycler instrument. Primers were obtained from a commercial vendor (Life Technologies) and shown in Table 1 .…”

Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure

“…Right ventricular pressure measurements were obtained using saline-filled catheters connected to pressure transducers (Cobe, Lakewood, CO) in an artificially ventilated, open-chest model, as previously described, with n=4–8 per treatment group (Paffett et al , 2012a; Paffett et al , 2012b). Continuous hemodynamic traces were recorded (AD Instruments) and right ventricular systolic pressure (RVSP) and right ventricular mean pressure (RVMP) were calculated from a stable recording of 20–30 seconds for each subject.…”