A Toll-Like Receptor 1/2 Agonist Augments Contractility in Rat Corpus Cavernosum.

INTRODUCTION: Activation of the innate immune Toll-like receptor 2 (TLR2) initiates inflammation and has been implicated in vascular dysfunction. Increased contraction and decreased relaxation responses in the penile vasculature lead to erectile dysfunction, a condition associated with inflammation. However, whether TLR2 activation plays a role in penile vascular function has not been established. AIM: We hypothesized that activation of the TLR 1/2 heterodimer (TLR1/2) augments contractile and impairs relaxation responses of corpus cavernosum and that these perturbations of vascular function are mediated by low nitric oxide (NO) availability and enhanced activity of the RhoA/Rho-kinase pathway. METHODS: Contraction and relaxation responses were measured in rat cavernosal strips using a myograph after incubation with a TLR1/2-activating ligand Pam3 CSK4 (Pam3), the TLR1/2 inhibitor CuCPT 22 (CuCPT), and inhibitors of NO synthase (LNAME) and Rho-kinase (Y27632). TLR2 protein expression was assessed by immunohistochemistry. MAIN OUTCOME MEASURES: Cumulative concentration response curves, sensitivity (pEC50), and maximal response (Emax ) of cavernosal strips to vasodilatory and vasocontractile agonists were compared between treatments. RESULTS: Pam3-treated cavernosal strips exhibited greater pEC50 and higher Emax to phenylephrine (PE) than control tissues. Inhibition of NO synthase increased Emax to PE in Pam3-treated cavernosal strips. Pam3 treatment reduced relaxation to Y27632 compared with control tissues. Inhibition of TLR1/2 activation with CuCPT returned the augmented contraction to PE and the decreased relaxation to Y27632 of Pam3-treated cavernosal strips to control values. CONCLUSIONS: The TLR1/2 heterodimer mediates augmented contraction and reduced relaxation in rat cavernosal strips. Thus, TLR1/2 activation antagonizes vascular responses crucial for normal erectile function and implicates immune activation in vasculogenic erectile dysfunction. Immune signaling via TLR2 may offer novel targets for treating inflammation-mediated vascular dysfunction in the penis.

Leukocyte telomere length in healthy Caucasian and African-American adolescents: relationships with race, sex, adiposity, adipokines, and physical activity.

OBJECTIVE: To examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents. STUDY DESIGN: Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed. RESULTS: Telomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio ± SE, 1.32 ± 0.01 vs 1.27 ± 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio ± SE, 1.31 ± 0.01 vs 1.27 ± 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls. CONCLUSIONS: This study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls.

Adiponectin moderates the relationship between adiposity and leptin in adolescents regardless of gender or race.

OBJECTIVES: To determine gender or race differences in associations between adiposity and leptin, and whether adiponectin moderates these relationships. METHODS: Subjects were 441 adolescents, 14-18 years old (44% black, 56% white; 50% female, 50% male). Percent body fat (%BF) was measured with dual-energy X-ray absorptiometry. Leptin and adiponectin were measured using immunoassays. RESULTS: Among the four groups (white boys, white girls, black boys and black girls), white girls had the highest adiponectin (p = 0.0017) and black girls had the highest leptin (p = 0.0164). Percent BF and leptin were positively correlated (p = 0.0164). The %BF-leptin relationship was stronger in boys than girls (p < 0.0001). Those with lower adiponectin had a stronger %BF-leptin relationship than those with high adiponectin in the entire sample (p = 0.0220). Statistical models were adjusted for age, race, gender and the interaction between race and gender. CONCLUSION: Our data suggest a protective metabolic interaction for adiponectin and lend additional support for obesity prevention strategies in adolescents.

FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth.

BACKGROUND: Genome-wide association studies found common variants in the fat mass and obesity-associated (FTO) gene associated with adiposity in Caucasians and Asians but the association was not confirmed in African populations. Association of FTO variants with insulin resistance and energy intake showed inconsistent results in previous studies. This study aimed to assess the influence of FTO variant rs9939609 on adiposity, insulin resistance, energy intake and physical activity in European - (EA) and African-American (AA) youth. METHODS: We conducted a cross-sectional study in EA and AA youths. One thousand, nine hundred and seventy-eight youths (48.2% EAs, 47.1% male, mean age 16.5 years) had measures of anthropometry. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Energy intake and physical activity were based on self report from up to 7 24-hour recalls. Physical activity was also measured by accelerometry. RESULTS: FTO rs9939609 was significantly associated with body mass index (BMI) (P = 0.01), weight (P = 0.03) and waist circumference (P = 0.04), with per-allele effects of 0.4 kg/m2, 1.3 kg and 0.8 cm, respectively. No significant association was found between rs9939609 and %BF, VAT, SAAT or insulin resistance (P > 0.05), or between rs9939609 and energy intake or vigorous physical activity (P > 0.05). No significant interactions of rs9939609 with ethnicity, gender, energy intake or physical activity were observed (P > 0.05). CONCLUSIONS: The FTO variant rs9939609 is modestly associated with BMI and waist circumference, but not with energy intake or physical activity. Moreover, these effects were similar for EAs and AAs. Improved understanding of the effect of the FTO variant will offer new insights into the etiology of excess adiposity.

Urinary prostasin: a possible biomarker for renal pressure natriuresis in black adolescents.

Prostasin is a membrane-bound/secretive serine protease interacting with aldosterone and the epithelial sodium channel in the kidney. We and others have previously proposed the concept of stress-induced pressure natriuresis (SIPN) where increased urinary sodium excretion (UNaV) is coupled with elevated blood pressure (BP) in response to behavioral stress in normotensive adolescents. This study thus aimed to test the relationship between prostasin and pressure natriuresis using the SIPN model. A cohort of 102 normotensive black adolescents (mean age: 17.0 +/- 1.2 y; 56% females) were placed on a controlled sodium (4000 +/- 200 mg/d) and potassium (2600 +/- 200 mg/d) diet for three days before testing. The SIPN protocol consisted of a 1-h baseline period, a 1-h stress period (competitive video game), and a 1-h recovery period. During the stress period, BP elevation was coupled with an increase in UNaV. Urinary prostasin concentration had more than a 2-fold reduction from baseline (38.4 +/- 32.7 ng/mL) to stress (17.2 +/- 16.0 ng/mL), and further declined during recovery (12.1 +/- 16.2 ng/mL) (p < 0.001). Urinary prostasin was inversely correlated with UNaV during stress (r = -0.43, p = 0.0001), even after being normalized by urinary creatinine. Our data suggest that urinary prostasin could be a novel biomarker and/or mechanism for renal pressure natriuresis in normotensive black adolescents.

Emerging molecular targets for treatment of erectile dysfunction: vascular and regenerative therapies on the horizon.

INTRODUCTION: Erectile dysfunction (ED) has reached epidemic proportions not expected to abate because of population aging and chronic diseases that accompany advanced age. Vasculopathy is a main cause, but damage to penile innervation also underlies many cases of ED. Phosphodiesterase inhibitor therapies do not help all men with ED, making the search for novel therapeutic drug and treatment targets of utmost importance. AIMS: To review the literature to identify potential new treatment targets to fill a gap in therapeutic options for men with ED, with a focus on treatments for vasculogenic ED, but including novel treatment targets for ED due to penile nerve damage, a frequent consequence of pelvic surgery in men. METHODS: The recent literature was searched for publications on in vitro, in vivo, pre-clinical and observational human studies, when available, that would identify potential new targets for ED therapies not previously, or not extensively reviewed. RESULTS: Literature searches identified microparticles, myeloperoxidase, and heme oxygenase-1 as emerging molecular targets to treat vasculogenic ED. Novel regenerative therapy targets, including sonic hedgehog, galanin, and cell-based treatments were also reviewed as potential future treatments for ED due to damage to penile innervation. CONCLUSION: Novel molecular targets and cell-based therapies offer great hope for advances in ED treatment. Concerns regarding efficacy, toxicity, off target effects, safety, and convenience apply to these targets; much work remains to confirm these as viable targets to pursue for effective ED treatments. To complement targets discussed in this review relevant review papers were cited for the interested reader. To complement targets discussed in this review relevant review papers were cited for the interested reader.

Lifestyle and socioeconomic-status modify the effects of ADRB2 and NOS3 on adiposity in European-American and African-American adolescents.

The aim of the study is to investigate the influence of and interaction between lifestyle behaviors (diet and physical activity (PA)) and single-nucleotide polymorphisms (SNPs) in obesity-candidate genes (ADRB2, APOB and NOS3) on general and central adiposity. Six-hundred-and-twenty-one European-American (EA) and African-American (AA) youths aged 13-19 years were classified by ethnicity (49% AA), gender (45% male), and socioeconomic status (SES). PA and dietary intake with up to seven 24-h recalls were reported for all subjects. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT), and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Reported energy intake (EI) and vigorous PA (VPA) were negative predictors of %BF and SAAT. Carriers of the NOS3 Asp298 allele had higher %BF only in the presence of an adverse environment (low SES). Compared to the most common NOS3 haplotype, homozygotes for haplotype A-non4r-Asp had 6.1% higher %BF. Significant interactions were revealed between the ADRB2 Arg16Gly SNP and VPA on VAT, SAAT and waist circumference (WC) such that Gly16 homozygotes may benefit less from increased VPA to reduce their weight. Genetic susceptibility to increased general and central adiposity is dependent on several factors, such as SES and vigorous exercise. Improved understanding of the joint effect of genes and lifestyle on adiposity will offer new insights into obesity and may provide new avenues for personalized prevention and treatment.

Relations of diet and physical activity to bone mass and height in black and white adolescents.

Because the development of healthy bodies during the years of growth has life-long health consequences, it is important to understand the early influences of diet and physical activity (PA). One way to generate hypotheses concerning such influences is to conduct cross-sectional studies of how diet and PA are related to different components of body composition. The subjects were 660 black and white adolescents. Total body bone mineral content (BMC) was measured with dual-energy X-ray absorptiometry; free-living diet and PA were assessed with 4-7 separate 24-h recalls. The main dietary variables investigated were: total energy intake, macronutrient distribution (%), dairy servings, vitamin D, and calcium. The main PA variables were hours of moderate PA (3-6 METs) and vigorous PA (>6 METs). BMC was higher in blacks than in whites (P<0.01) and it increased more in boys than in girls (age by sex interaction) as age increased (P<0.01). After adjustment for age, race and sex, higher levels of BMC were associated with higher levels of energy intake, dairy servings, calcium, vitamin D, and vigorous PA (all P 's<0.05). In the multivariable model, significant and independent proportions of the variance in BMC were explained by race, the age by sex interaction, calcium, and vigorous PA (all P 's<0.01). When height was used as the outcome variable, similar diet results were obtained; however, there was a sex by vigorous PA interaction, such that vigorous PA was associated with height only in the girls. These data are consistent with the hypothesis that the bone mass and height of growing youths are positively influenced by higher dietary intake of energy and dairy foods, along with sufficient amounts of vigorous PA. This hypothesis needs to be tested in randomized controlled trials.

Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults.

BACKGROUND: A growing body of evidence has linked vitamin D deficiency to increased risk of cardiovascular disease. Vitamin D deficiency is also more common in African Americans for whom an increased cardiovascular disease risk exists. This study sought to test the hypothesis that 16 weeks of 60,000 IU monthly supplementation of oral vitamin D(3) would improve flow-mediated dilation (FMD) in African Americans, whereas no change would be observed in the placebo group. METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted. Fifty-seven African-American adults were randomly assigned to either the placebo group or vitamin D group. RESULTS: Following 16 weeks of placebo (n = 23; mean age 31 ± 2 years) or 60,000 IU monthly oral vitamin D(3) (n = 22; mean age 29 ± 2 years), serum concentrations of 25-hydroxyvitamin D (25(OH)D) increased from 38.2 ± 3.0 to 48.7 ± 3.2 nmol/l and 34.3 ± 2.2 to 100.9 ± 6.6 nmol/l, respectively. No changes in serum parathyroid hormone (PTH), serum calcium, or urine calcium/creatinine were observed following either treatment. Following 16 weeks of treatment, significant improvements in FMD were only observed in the vitamin D group (1.8 ± 1.3%), whereas the placebo group had no change (-1.3 ± 0.6%). Similarly, the vitamin D group exhibited an increase in absolute change in diameter (0.005 ± 0.004 cm) and FMD/shear (0.08 ± 0.04 %/s(-1), area under the curve (AUC) × 10(3)) following treatment, whereas no change (-0.005 ± 0.002 cm and -0.02 ± 0.02 %/s(-1), AUC, respectively) was observed following placebo. CONCLUSION: Supplementation of 60,000 IU monthly oral vitamin D(3) (~2,000 IU/day) for 16 weeks is effective at improving vascular endothelial function in African-American adults.

Sex dimorphisms in inflammatory markers and adiposity in African-American youth.

OBJECTIVE: There are demonstrated sex differences in the association between adiposity and inflammation in adults. Our aim was to determine sex differences in inflammatory markers and in the association between adiposity and inflammation in a sample of African-American adolescents. METHODS: Adiposity variables including body mass index (BMI), waist circumference, weight, total fat, trunk fat, and inflammatory markers including interleukin-6 (IL-6), leptin, monocyte chemotactic protein 1 (MCP1), C-reactive Protein (CRP), adiponectin were examined in 166 (53% female) African-American adolescents, aged 14-19 years. Total fat and trunk fat were measured using Dual-Energy X-ray Absorptiometry (DXA). RESULTS: Results revealed males had higher weight (p=0.01); females had higher BMI, trunk fat, and total fat (p's <0.01). With inflammation, males had higher MCP1 (p=0.024); females had higher leptin (p<0.001), adiponectin (p=0.006), and IL-6 (p=0.026). Partial correlations in males indicated associations of adiposity variables with leptin, adiponectin (all p's <0.01), and CRP (p<0.05); in females, leptin, CRP, and IL-6 were associated with adiposity variables (all p's <0.05). multiple regression analyses revealed female adiposity variables predicted CRP, (R(2)=0.254), IL-6 (R(2)=0.167), and MCP1 (R(2)=0.220). Adiposity variables in males predicted lower adiponectin (R(2)=0245). For both, leptin was predicted by adiposity (males R(2)=0.420 and females R(2)=0.410). CONCLUSIONS: Data indicate clear sex dimorphisms in the associations between inflammatory markers and adiposity in African-American adolescents, suggesting that preventive measures and treatments for adolescent obesity may need to be sex-specific.

Low 25-hydroxyvitamin D levels in adolescents: race, season, adiposity, physical activity, and fitness.

OBJECTIVES: The objectives were to characterize the vitamin D status of black and white adolescents residing in the southeastern United States (latitude: approximately 33 degrees N) and to investigate relationships with adiposity. METHODS: Plasma 25-hydroxyvitamin D levels were measured with liquid chromatography-tandem mass spectroscopy for 559 adolescents 14 to 18 years of age (45% black and 49% female). Fat tissues, physical activity, and cardiovascular fitness also were measured. RESULTS: The overall prevalences of vitamin D insufficiency (<75 nmol/L) and deficiency (< or = 50 nmol/L) were 56.4% and 28.8%, respectively. Black versus white subjects had significantly lower plasma 25-hydroxyvitamin D levels in every season (winter, 35.9 + or - 2.5 vs 77.4 + or - 2.7 nmol/L; spring, 46.4 + or - 3.5 vs 101.3 + or - 3.5 nmol/L; summer, 50.7 + or - 4.0 vs 104.3 + or - 4.0 nmol/L; autumn, 54.4 + or - 4.0 vs 96.8 + or - 2.7 nmol/L). With adjustment for age, gender, race, season, height, and sexual maturation, there were significant inverse correlations between 25-hydroxyvitamin D levels and all adiposity measurements, including BMI percentile (P = .02), waist circumference (P < .01), total fat mass (P < .01), percentage of body fat (P < .01), visceral adipose tissue (P = .015), and subcutaneous abdominal adipose tissue (P = .039). There were significant positive associations between 25-hydroxyvitamin D levels and vigorous physical activity (P < .01) and cardiovascular fitness (P = .025). CONCLUSIONS: Low vitamin D status is prevalent among adolescents living in a year-round sunny climate, particularly among black youths. The relationships between 25-hydroxyvitamin D levels, adiposity, physical activity, and fitness seem to be present in adolescence.

A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness.

CONTEXT: Vitamin D insufficiency/deficiency is commonly observed in black youth. OBJECTIVE: The aim was to determine 25-hydroxyvitamin D [25(OH)D] in response to 2000 IU vitamin D supplementation over time; to evaluate the relation between 25(OH)D concentrations and total body fat mass by dual-energy x-ray absorptiometry; and to determine whether vitamin D supplementation improves arterial stiffness measured by pulse wave velocity (PWV). DESIGN: We conducted a randomized, blinded, controlled clinical trial. SETTING AND PARTICIPANTS: Forty-nine normotensive black boys and girls, aged 16.3 ± 1.4 yr, were randomly assigned to either the control group (400 IU/d; n = 24) or the experimental group (2000 IU/d; n = 25). RESULTS: Plasma 25(OH)D values at baseline and at 4, 8, and 16 wk were 34.0 ± 10.6, 44.9 ± 9.4, 51.2 ± 11.1, and 59.8 ± 18.2 nmol/liter, respectively, for the control group; and 33.1 ± 8.7, 55.0 ± 11.8, 70.9 ± 22.0, and 85.7 ± 30.1 nmol/liter, respectively, for the experimental group. The experimental group vs. the control group reached significantly higher 25(OH)D concentrations at 8 and 16 wk, respectively. Partial correlation analyses indicated that total body fat mass at baseline was significantly and inversely associated with 25(OH)D concentrations in response to the 2000-IU supplement across time. Furthermore, carotid-femoral PWV increased from baseline (5.38 ± 0.53 m/sec) to posttest (5.71 ± 0.75 m/sec) in the control group (P = 0.016), whereas in the experimental group carotid-femoral PWV decreased from baseline (5.41 ± 0.73 m/sec) to posttest (5.33 ± 0.79 m/sec) (P = 0.031). CONCLUSION: Daily 2000 IU vitamin D supplementation may be effective in optimizing vitamin D status and counteracting the progression of aortic stiffness in black youth. Plasma 25(OH)D concentrations in response to the 2000 IU/d supplementation are negatively modulated by adiposity.