Citations

Objective— Hypertension and hypercholesterolemia might interfere with renal repair mechanisms. We hypothesized that simvastatin improves the survival of endothelial progenitor cells (EPC) in the renal microenvironment imposed by concurrent renovascular hypertension and dietary hypercholesterolemia (HTC). Methods and Results— Pigs were studied after 12 weeks of no intervention (n=6), HTC (n=6), or HTC+ oral simvastatin supplementation (80 mg/day, n=5). EPC were also isolated and studied in vitro after exposure to the proapoptotic oxidized low-density lipoprotein with or without coincubation with simvastatin. Renal hemodynamics, function, and endothelial function were evaluated in vivo, and the number of CD34+/KDR+ EPC, apoptosis, oxidative stress, inflammation, and fibrosis in renal tissue studied ex vivo. Compared with normal kidney, the HTC kidney showed endothelial dysfunction and increased oxidative stress, interstitial macrophage filtration, and fibrosis. The number of EPC in the kidney increased, as did their apoptosis (0.85±0.24% versus 0.22±0.07%, P <0.05 versus normal). Simvastatin did not affect blood pressure, cholesterol levels, basal renal function, or number of renal EPC in HTC, but it improved endothelial function; blunted renal oxidative stress, inflammation, and fibrosis; and attenuated EPC apoptosis (to 0.37±0.09%, P <0.05 versus HTC). Simvastatin also significantly decreased oxidized low-density lipoprotein–induced EPC apoptosis in vitro. Conclusion— EPC are recruited but undergo apoptosis in the HTC kidney, likely because of a hostile microenvironment. Simvastatin rescues renal repair mechanisms in HTC and counteracts renal damage, which may account for its protective effects on the kidney during exposure to cardiovascular risk factors.

Antispasmodics are used clinically to treat a variety of gastrointestinal disorders by inhibition of smooth muscle contraction. The main pathway for smooth muscle Ca2+entry is through L-type channels; however, there is increasing evidence that T-type Ca2+channels also play a role in regulating contractility. Otilonium bromide, an antispasmodic, has previously been shown to inhibit L-type Ca2+channels and colonic contractile activity. The objective of this study was to determine whether otilonium bromide also inhibits T-type Ca2+channels. Whole cell currents were recorded by patch-clamp technique from HEK293 cells transfected with cDNAs encoding the T-type Ca2+channels, CaV3.1 (α1G), CaV3.2 (α1H), or CaV3.3 (α1I) alpha subunits. Extracellular solution was exchanged with otilonium bromide (10−8to 10−5M). Otilonium bromide reversibly blocked all T-type Ca2+channels with a significantly greater affinity for CaV3.3 than CaV3.1 or CaV3.2. Additionally, the drug slowed inactivation in CaV3.1 and CaV3.3. Inhibition of T-type Ca2+channels may contribute to inhibition of contractility by otilonium bromide. This may represent a new mechanism of action for antispasmodics and may contribute to the observed increased clinical effectiveness of antispasmodics compared with selective L-type Ca2+channel blockers.

Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway.

Abstract We measured type I procollagen carboxyl-terminal propeptide (PICP) by a commercial radioimmunoassay and amino-terminal propeptide (PINP) by an enzyme-linked immunosorbent assay (ELISA) developed in our laboratory in serum from 75 normal women, 10 growing girls, 84 normal men, and 197 patients with various metabolic bone diseases. The molar concentrations of serum PINP were 100-fold higher than those of PICP, suggesting differences in the metabolism of PICP and PINP. In normal women, serum PICP values correlated positively with age and serum PINP values correlated negatively with age (r = 0.28 and −0.32, respectively; P = 0.02). In normal men, however, PICP correlated negatively with age (r = −0.32, P = 0.003) whereas PINP did not change. As assessed by Z scores (SD from age- and sex-specific predicted normal mean), changes in serum PICP and PINP values were concordant in hypoparathyroidism (mean Z scores for PICP and PINP, −0.63 and −1.48, respectively) and Cushing's syndrome (0.50 and 0.40) but were discordant in acromegaly (0.78 and −0.68), hyperthyroidism (1.33 and −0.66), untreated postmenopausal osteoporosis (-0.11 and 0.40), fluoride-treated postmenopausal osteoporosis (-0.61 and 1.08), Paget's disease (4.05 and −0.20), and chronic renal failure (1.45 and −0.50). With either assay, deviations from normal were less pronounced than the deviations of concurrently measured serum osteocalcin and bone alkaline phosphatase values. The deviations in these latter two values agreed better with those of PICP than with those of PINP, except in untreated or fluoride-treated osteoporotic patients. We conclude that for assessing abnormalities in bone formation in metabolic bone diseases, assays for serum PICP or PINP generally are inferior to those for serum osteocalcin and bone alkaline phosphatase.

Abstract Signal transducers and activators of transcription 3 (STAT3) is constitutively active in human pancreatic cancer cells and can promote cell growth and apoptosis resistance that contribute to tumorigenesis. We determined if sorafenib, a multikinase inhibitor, can induce apoptosis by targeting STAT3 signaling to enhance apoptosis induction by tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Human pancreatic cancer cell lines (PANC-1 and BxPC-3) were preincubated with sorafenib (Nexavar) alone or followed by TRAIL. Apoptosis was determined by Annexin V labeling, caspase cleavage, and Bax/Bak activation. Protein expression was analyzed by immunoblotting. Knockdown of STAT3, Mcl-1, and Bim were achieved by lentiviral small hairpin RNA. Adenoviral dominant-negative or retroviral constitutively active (CA) STAT3 were also used. Sorafenib inhibited constitutive STAT3 phosphorylation (Tyr705) and suppressed Mcl-1 and Bcl-xL proteins in a dose- and time-dependent manner. CA-STAT3 overexpression was shown to attenuate caspase-3 cleavage and suppression of Mcl-1 by sorafenib. STAT3 knockdown or a DN STAT3 was shown to downregulate Mcl-1 and Bcl-xL and to sensitize cells to TRAIL-mediated apoptosis. Treatment with sorafenib enhanced TRAIL-induced Annexin V staining and release of mitochondrial cytochrome c and AIF. Because the BH3-only Bim protein is a potent inducer of mitochondrial apoptosis, Bim knockdown was shown to attenuate caspase-3, caspase-9 cleavage, and Bax/Bak activation by sorafenib plus TRAIL. The suppression of STAT3 by genetic means or using sorafenib was shown to downregulate Mcl-1 and Bcl-xL and to sensitize cells to TRAIL-mediated apoptosis. These data indicate that targeting STAT3 may enhance treatment efficacy against pancreatic cancer. Mol Cancer Ther; 9(3); 742–50

This descriptive population study of 307 public high school students, ages 15 to 17 years, was performed to establish reference ranges for orthostatic changes in heart rate and blood pressure in adolescents, and to identify influential variables. Noninvasive measurements of blood pressure and heart rate were obtained. Reference ranges for orthostatic heart rate change in this population at 2 minutes were –2 to +41 beats per minute and at 5 minutes were –1 to +48 beats per minute. Orthostatic blood pressure changes were within the adult range for 98% of adolescents tested. One-third of participants experienced orthostatic symptoms during testing. In conclusion, this study shows that orthostatic symptoms and large orthostatic heart rate changes occur in adolescents. This suggests that the current orthostatic heart rate criterion aiding the diagnosis of adult orthostatic intolerance syndromes is likely not appropriate for adolescents and should be reevaluated.

Abstract Aims Hospitalized heart failure (HF) patients are at high risk for death and readmission. We examined the incremental value of data obtained 1 week after HF hospital discharge in predicting mortality and readmission. Methods and results In the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with tolvaptan, 1528 hospitalized patients (ejection fraction ≤40%) with a physical examination, laboratories, and health status [Kansas City Cardiomyopathy Questionnaire (KCCQ)] assessments 1 week after discharge were included. The ability to predict 1 year cardiovascular rehospitalization and mortality was assessed with Cox models, c-statistics, and the integrated discrimination improvement (IDI). Not using a beta-blocker, rales, pedal oedema, hyponatraemia, lower creatinine clearance, higher brain natriuretic peptide, and worse health status were independent risk factors for rehospitalization and death. The c-statistic for the base model (history and medications) was 0.657. The model improved with physical examination, laboratory, and KCCQ results, with IDI increases of 4.9, 7.0, and 3.2%, respectively (P &lt; 0.001 each). The combination of all three offered the greatest incremental gain (c-statistic 0.749; IDI increase 10.8%). Conclusion Physical examination, laboratories, and KCCQ assessed 1 week after discharge offer important prognostic information, suggesting that all are critical components of outpatient evaluation after HF hospitalization.