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

Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension

Ozone Inhalation Impairs Coronary Artery Dilation via Intracellular Oxidative Stress: Evidence for Serum-Borne Factors as Drivers of Systemic Toxicity

Photograph used for a newspaper owned by the Oklahoma Publishing Company. Caption: "(Photo of a man on a service truck swepping of the service bed, trash in the background, and more.)

Muscle RING finger-1 promotes a maladaptive phenotype in chronic hypoxia-induced right ventricular remodeling.

Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent 201Tl-chloride and cell death agent 99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension

Right ventricular remodeling following MCT injection was evident from the ratio of right ventricular mass to left ventricular plus septal mass (RV/LVS); this effect was diminished by resveratrol treatment (A).

<p>No obvious effect on lung remodeling or edema formation was noted at 42 days post-MCT injection (B). Right ventricular enlargement was evident at 3–4 weeks in MCT/water-treated rats (M/W), with some resolution in MCT/resveratrol rats (M/R) from SPECT images of ²⁰¹Thallium (C). No apparent changes were noted in saline/water (S/W) or saline/resveratrol (S/R) control rats. Notably, septal indentation, a result of increased right ventricular pressure, was evident as early as 2 weeks post-MCT (D). Asterisks indicate significant (P<0.05) elevation over other groups by ANOVA with Newman-Keuls Posthoc Comparison Test.</p

Global cardiac perfusion, as assessed by 201Thallium detection, showed no significant differences between groups or trends across the 42-day imaging period.

<p>Global cardiac perfusion, as assessed by 201Thallium detection, showed no significant differences between groups or trends across the 42-day imaging period.</p

Quantitative assessments of ⁹⁹Tc-annexin energy from the cardiac region, without consideration of pulmonary signals, are shown graphically.

<p>A severe induction of cardiac apoptosis was observed in one MCT-only rat, depicted from two positions in the figure to the right. Asterisks indicate significant (P<0.05) elevation in the MCT-only group compared to other groups by 2-way (time, treatment) ANOVA.</p

Left-sided cardiac cycle changes over the 6-week period of MCT-induced PAH pathogenesis (A).

<p>ECG-gating methods enabled the distribution of ²⁰¹Thallium decay detections into 8 bins between electrocardiographic R waves. Cardiac cycles from end diastole (ED) to subsequent end diastole are shown, with end systole (ES) in the middle. Both treatment groups showed nearly identical left ventricular function at baseline and up until week 3 post-MCT injection. At week 3, and progressing through week 5, a significant reduction in the overall volume of the left ventricle was noted. This corresponded with increased ejection fraction (B) and no net change in stroke volume (C) over the same time period. Asterisks indicate significant (P<0.05) elevation over other groups by 2-way (time, treatment) ANOVA.</p

Monocrotaline induced significant changes in right ventricular systolic (A) and mean (B) pressure, which were alleviated by late treatment with resveratrol in the drinking water.

<p>Right-sided cardiac contractility, as assessed by +<i>d</i>P/<i>d</i>t_max from the RV pressure wave, was significantly elevated in the MCT-treated rats, and again reduced to control levels by resveratrol (C). No heart rate (HR) differences among the groups were noted, confirming a consistent level of anesthetic depth between groups during hemodynamic assessment (D). Asterisks indicate significant (P<0.05) elevation over other groups by ANOVA with Newman-Keuls Posthoc Comparison Test.</p