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

Online Reviewers Face Feds Over Right to Stay Anonymous

[quote] American University law professor Jennifer Daskal, who writes on issues related to privacy and criminal law, called the law around the government’s ability to lift the veil on anonymous online speech “pretty unresolved.” She said the case is about the right of “people to speak anonymously on a range of a different websites without running the risk of revealing their identity to the government.

Online Reviewers Face Feds Over Right to Stay Anonymous

[quote] American University law professor Jennifer Daskal, who writes on issues related to privacy and criminal law, called the law around the government’s ability to lift the veil on anonymous online speech “pretty unresolved.” She said the case is about the right of “people to speak anonymously on a range of a different websites without running the risk of revealing their identity to the government.

The Interplanetary Magnetic Field Observed by Juno Enroute to Jupiter

The Juno spacecraft was launched on 5 August 2011 and spent nearly 5 years traveling through the inner heliosphere on its way to Jupiter. The Magnetic Field Investigation was powered on shortly after launch and obtained vector measurements of the interplanetary magnetic field (IMF) at sample rates from 1 to 64 samples/second. The evolution of the magnetic field with radial distance from the Sun is compared to similar observations obtained by Voyager 1 and 2 and the Ulysses spacecraft, allowing a comparison of the radial evolution between prior solar cycles and the current depressed one. During the current solar cycle, the strength of the IMF has decreased throughout the inner heliosphere. A comparison of the variance of the normal component of the magnetic field shows that near Earth the variability of the IMF is similar during all three solar cycles but may be less at greater radial distances

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

Differential Induction of Cardiac Hypertrophy/Failure Transcripts in MuRF^-/- & <i>MuRF1 Tg+</i> Mice Following CH.

<p>Effects of CH-induced PH on relative RV transcript expression of <i>(A)</i> SM a-actin, <i>(B)</i> MyHC-b, <i>(C)</i> BNP and <i>(D)</i> mtND2 DNA content from <i>MuRF1 -/-</i> and MuRF1 Tg+ mice. BNP, MyHC-b and SM a-actin expression normalized to TATA binding protein. MtND2 DNA content normalized to 18S DNA. N = 5 per group, *p<0.05 vs respective normoxic control; #p<0.05 vs chronic hypoxia Tg⁺; **p<0.05 vs respective WT.</p

Hypoxia-induced right ventricular remodeling is enhanced by MuRF1 deletion, while cardiac-specific MuRF1 overexpression leads to a maladaptive dilated phenotype.

<p>(A) Chronic hypoxia induced predictable increases in RV/LVS, more so in the <i>MuRF1 -/-</i> mice than in WT. Interestingly, cardiac-specific overexpression of this atrophy-mediating ubiquitin ligase had no protective effect in terms of net hypertrophy of the right ventricle and in fact led to exacerbation of hypoxia-induced RVH relative to WT (*significantly greater than all control groups, <i>p</i><0.01; **significantly greater than all control groups and WT hypoxia, <i>p</i><0.01; ***significantly greater than all other groups, <i>p</i><0.01). (B) Axial SPECT/CT cross-section images obtained at diastole reveal marked hypertrophy of the RV in hypoxia-exposed mice, with the appearance of dilation in the MuRF1 Tg+ mice. (C) Right ventricular weight to chamber volume ratio (D) ejection fraction and (E) RV systolic and diastolic volumes determined from ECG-gated SPECT/CT images are shown. As RV wall motion was difficult to image in normoxia mice, all genotypes are pooled. (N = 3-6 per group; *significantly lower than KO, Hypoxia mice, <i>p</i><0.05).</p

Body weight response to CH is evident in global <i>MuRF1 -/-</i> mice compared to cardiac-specific MuRF1 Tg⁺ mice.

<p>Longitudinal weight change profile during chronic hypoxia exposure illustrates global MuRF1 deletion attenuates weight loss with similar gain to WT <i>(A)</i>, whereas MuRF1 Tg⁺ mice have similar weight loss and gain compared to WT <i>(B)</i>. N = 5-6 per group, *p<0.05 from WT.</p

WT C57BL/6 mouse response to hypoxia in terms of right ventricular systolic pressure (A), right ventricular hypertrophy (B), right ventricular expression of B-type natriuretic peptide mRNA (C) and right MuRF1 mRNA (D).

<p>Asterisks denote significant difference from normoxic controls (p<0.05) by two-tailed t-test (N = 7-8 per group).</p