Citations

GH is an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating “endocrine” IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-7. LiGHRKO mice were smaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found in GH transgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-I mRNA levels were significantly increased in skeletal muscle and select adipose tissue depots. Grip strength was increased in LiGHRKO mice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.

Obesity associated with metabolic derangements (ObM) worsens the prognosis of patients with coronary artery stenosis (CAS), but the underlying cardiac pathophysiologic mechanisms remain elusive. We tested the hypothesis that ObM exacerbates cardiomyocyte loss distal to moderate CAS. Obesity-prone pigs were randomized to four groups ( n = 6 each): lean-sham, ObM-sham, lean-CAS, and ObM-CAS. Lean and ObM pigs were maintained on a 12-wk standard or atherogenic diet, respectively, and left circumflex CAS was then induced by placing local-irritant coils. Cardiac structure, function, and myocardial oxygenation were assessed 4 wk later by computed-tomography and blood oxygenation level dependent (BOLD) MRI, the microcirculation with micro-computed-tomography, and injury mechanisms by immunoblotting and histology. ObM pigs showed obesity, dyslipidemia, and insulin resistance. The degree of CAS (range, 50–70%) was similar in lean and ObM pigs, and resting myocardial perfusion and global cardiac function remained unchanged. Increased angiogenesis distal to the moderate CAS observed in lean was attenuated in ObM pigs, which also showed microvascular dysfunction and increased inflammation (M1-macrophages, TNF-α expression), oxidative stress (gp91), hypoxia (BOLD-MRI), and fibrosis (Sirius-red and trichrome). Furthermore, lean-CAS showed increased myocardial autophagy, which was blunted in ObM pigs (downregulated expression of unc-51-like kinase-1 and autophagy-related gene-12; P < 0.05 vs. lean CAS) and associated with marked apoptosis. The interaction diet xstenosis synergistically inhibited angiogenic, autophagic, and fibrogenic activities. ObM exacerbates structural and functional myocardial injury distal to moderate CAS with preserved myocardial perfusion, possibly due to impaired cardiomyocyte turnover.

Abstract Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.

Abstract Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion–induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference–mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. Cancer Res; 74(6); 1870–80. ©2014 AACR.

Blood oxygen level-dependent (BOLD) MRI data of kidney, while indicative of tissue oxygenation level (Po2), is in fact influenced by multiple confounding factors, such as R2, perfusion, oxygen permeability, and hematocrit. We aim to explore the feasibility of extracting tissue Po2 from renal BOLD data. A method of two steps was proposed: first, a Monte Carlo simulation to estimate blood oxygen saturation (SHb) from BOLD signals, and second, an oxygen transit model to convert SHb to tissue Po2. The proposed method was calibrated and validated with 20 pigs (12 before and after furosemide injection) in which BOLD-derived tissue Po2 was compared with microprobe-measured values. The method was then applied to nine healthy human subjects (age: 25.7 ± 3.0 yr) in whom BOLD was performed before and after furosemide. For the 12 pigs before furosemide injection, the proposed model estimated renal tissue Po2 with errors of 2.3 ± 5.2 mmHg (5.8 ± 13.4%) in cortex and −0.1 ± 4.5 mmHg (1.7 ± 18.1%) in medulla, compared with microprobe measurements. After injection of furosemide, the estimation errors were 6.9 ± 3.9 mmHg (14.2 ± 8.4%) for cortex and 2.6 ± 4.0 mmHg (7.7 ± 11.5%) for medulla. In the human subjects, BOLD-derived medullary Po2 increased from 16.0 ± 4.9 mmHg (SHb: 31 ± 11%) at baseline to 26.2 ± 3.1 mmHg (SHb: 53 ± 6%) at 5 min after furosemide injection, while cortical Po2 did not change significantly at ∼58 mmHg (SHb: 92 ± 1%). Our proposed method, validated with a porcine model, appears promising for estimating tissue Po2 from renal BOLD MRI data in human subjects.

Background The utility of longitudinal, circumferential, and radial strain and strain rate in determining prognosis in chronic heart failure is not well established. Methods and Results In 416 patients with chronic systolic heart failure, we performed speckle‐tracking analyses of left ventricular longitudinal, circumferential, and radial strain and strain rate on archived echocardiography images (30 frames per second). Cox regression models were used to determine the associations between strain and strain rate and risk of all‐cause mortality, cardiac transplantation, and ventricular‐assist device placement. The area under the time‐dependent ROC curve ( AUC ) was also calculated at 1 year and 5 years. Over a maximum follow‐up of 8.9 years, there were 138 events (33.2%). In unadjusted models, all strain and strain rate parameters were associated with adverse outcomes ( P <0.001). In multivariable models, all parameters with the exception of radial strain rate ( P =0.11) remained independently associated, with patients in the lowest tertile of strain or strain rate parameter having a ≈2‐fold increased risk of adverse outcomes compared with the reference group ( P <0.05). Addition of strain to ejection fraction ( EF ) led to a significantly improved AUC at 1 year (0.697 versus 0.633, P =0.032) and 5 years (0.700 versus 0.638, P =0.001). In contrast, strain rate did not provide incremental prognostic value to EF alone. Conclusions Longitudinal and circumferential strain and strain rate, and radial strain are associated with chronic heart failure prognosis. Strain provides incremental value to EF in the prediction of adverse outcomes, and with additional study may be a clinically relevant prognostic tool.

Abstract A 14-day orbital spaceflight was performed using ovariectomized Fisher 344 rats to determine the combined effects of estrogen deficiency and near weightlessness on tibia radial bone growth and cancellous bone turnover. Twelve ovariectomized rats with established cancellous osteopenia were flown aboard the space shuttle Columbia (STS-62). Thirty ovariectomized rats were housed on earth as ground controls: 12 in animal enclosure modules, 12 in vivarium cages, and 6 killed the day of launch for baseline measurements. An additional 18 ovary-intact rats were housed in vivarium cages as ground controls: 8 rats were killed as baseline controls and the remaining 10 rats were killed 14 days later. Ovariectomy increased periosteal bone formation at the tibia-fibula synostosis; cancellous bone resorption and formation in the secondary spongiosa of the proximal tibial metaphysis; and messenger RNA (mRNA) levels for the prepro-α2(1) subunit of type 1 collagen, osteocalcin, transforming growth factor-β, and insulin-like growth factor I in the contralateral proximal tibial metaphysis and for the collagen subunit in periosteum pooled from tibiae and femora and decreased cancellous bone area. Compared to ovariectomized weight-bearing rats, the flight group experienced decreases in periosteal bone formation, collagen subunit mRNA levels, and cancellous bone area. The flight rats had a small decrease in the cancellous mineral apposition rate, but no change in the calculated bone formation rate. Also, spaceflight had no effect on cancellous osteoblast and osteoclast perimeters or on mRNA levels for bone matrix proteins and signaling peptides. On the other hand, spaceflight resulted in an increase in bone resorption, as ascertained from the diminished retention of a preflight fluorochrome label. This latter finding suggests that osteoclast activity was increased. In a follow-up ground-based experiment, unilateral sciatic neurotomy of ovariectomized rats resulted in cancellous bone loss in the unloaded limb in excess of that induced by gonadal hormone deficiency. This additional bone loss was arrested by estrogen replacement. We conclude from these studies that estrogen alters the expression of signaling peptides believed to mediate skeletal adaptation to changes in mechanical usage and likewise modifies the skeletal response to mechanical unloading.