[Show abstract][Hide abstract] ABSTRACT: Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II).
[Show abstract][Hide abstract] ABSTRACT: Prostaglandin E2 (PGE2) is elevated during cardiac injury and we have previously shown that mice lacking the PGE2 EP4 receptor display dilated cardiomyopathy (DCM) with increased expression of the membrane type matrix metalloproteinase, MMP-14. We thus hypothesized that PGE2 regulates expression of MMP-14 and also affects fibroblast migration. Primary cultures of neonatal rat ventricular fibroblasts (NVFs) were used to test the effects of PGE2. Gene and protein expression was assessed by real time RT-PCR and Western blot, MMP activity was determined by zymography and migration of NVF was assessed by motility in a transwell system. PGE2 reduced expression of MMP-14 and these effects were antagonized by an EP4 antagonist. An EP4 agonist mimicked the effect of PGE2. PGE2 also increased mRNA and protein levels of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of MMP activation. However, PGE2-stimulation of PAI-1 was mediated by the EP1/EP3 receptor and not EP4. Migration of NVF was assessed by motility in a transwell system. Treatment of NVFs with PGE2 reduced the number of cells migrating toward 10% FCS. Treatment with the EP2 agonist also reduced migration but did not affect MMP-14 expression or PAI-1. Our results suggest that PGE2 utilizes different receptors and mechanisms to ultimately decrease MMP expression and NVF migration.
Prostaglandins & other lipid mediators 09/2014; · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thymosin β4 (Tβ4) promotes cell survival, angiogenesis, tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg/kg/day i.p. via osmotic minipump) for 7 days or 5 weeks. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis and interstitial collagen fraction (ICF) histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of intercellular adhesion molecule-1 (ICAM-1) and p53 by immunoblot. Tβ4 reduced cardiac rupture that was associated with decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, decrease in gelatinolytic activity and ICAM-1 and p53 expression, as well as the increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, and markedly reduced ICF and increased capillary density. In murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.
American journal of physiology. Heart and circulatory physiology. 07/2014;
[Show abstract][Hide abstract] ABSTRACT: The afferent arteriole (Af-Art) controls glomerular capillary pressure, an important determinant of glomerular injury. Af-Art myogenic response is mediated by ATP, and ATP signaling is in turn mediated by 20-HETE. Dahl salt-sensitive rats (Dahl SS) have decreased renal 20-HETE production. We hypothesized that Dahl SS have an impaired myogenic response and constrictor response to ATP, due to decreased 20-HETE. Af-Arts from Dahl SS or Dahl salt resistant rats (Dahl SR) were microdissected and perfused. When myogenic response was induced by increasing Af-Art perfusion pressure from 60 to 140 mmHg, luminal Af-Art diameter decreased in Dahl SR but not in Dahl SS (-3.1±0.8 vs. 0.5±0.8 µm, P<0.01). The 20-HETE antagonist 20-HEDE (10(-6)M) blocked the myogenic response in Dahl SR but had no effect in Dahl SS. Addition of a subconstrictor concentration of 20-HETE (but not a subconstrictor concentration of norepinephrine) restored the myogenic response in Dahl SS. We then perfused Af-Arts at 60 mmHg and tested the effects of the ATP analog α,β-methylene-ATP (10-6M). Maximum ATP-induced constriction was attenuated in Dahl SS compared to Dahl SR (1.5±0.5 vs. 7.4±0.8 µm, P<0.001). 20-HEDE attenuated ATP-induced Af-Art constriction in Dahl SR but not in Dahl SS, and consequently, ATP-induced constriction was no longer different between strains. In conclusion, Dahl SS have an impaired myogenic response and ATP-induced Af-Art constriction due to a decrease in Af-Art 20-HETE. The impaired myogenic responses may contribute to the nephrosclerosis that develops in Dahl SS.
American journal of physiology. Renal physiology 07/2014; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Infection is the second leading cause of death in hemodialysis patients. Catheter-related bloodstream infection and infection-related mortality have not improved in this population over the past two decades. This study evaluated the impact of a prophylactic antibiotic lock solution on the incidence of catheter-related bloodstream infection and mortality.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective, multicenter, observational cohort study compared the effectiveness of two catheter locking solutions (gentamicin/citrate versus heparin) in 555 hemodialysis patients dialyzing with a tunneled cuffed catheter between 2008 and 2011. The groups were not mutually exclusive. Rates of catheter-related bloodstream infection and mortality hazards were compared between groups.RESULTS: The study population (n=555 and 1350 catheters) had a median age of 62 years (interquartile range=41-83 years), with 50% men and 71% black. There were 427 patients evaluable in the heparin period (84,326 days) and 322 patients evaluable in the antibiotic lock period (71,192 days). Catheter-related bloodstream infection in the antibiotic lock period (0.45/1000 catheter days) was 73% lower than the heparin period (1.68/1000 catheter days; P=0.001). Antibiotic lock use was associated with a decreased risk of catheter-related bloodstream infection compared with heparin (risk ratio, 0.23; 95% confidence interval, 0.13 to 0.38 after multivariate adjustment). Cox proportional hazards modeling found that antibiotic lock was associated with a reduction in mortality (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58 in unadjusted analyses; hazard ratio, 0.32; 95% confidence interval, 0.14 to 0.75 after multivariate adjustment). The rate of gentamicin-resistant organisms decreased (0.40/1000 person-years to 0.22/1000 person-years) in the antibiotic lock period (P=0.01).CONCLUSIONS: The results of this study show that the use of a prophylactic, gentamicin/citrate lock was associated with a substantial reduction in catheter-related bloodstream infection and is the first to report a survival advantage of antibiotic lock in a population at high risk of infection-related morbidity and mortality.
Clinical journal of the American Society of Nephrology : CJASN. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Increasing Na delivery to epithelial Na channels (ENaC) in the connecting tubule (CNT) dilates the afferent arteriole (Af-Art), a process we call connecting tubule glomerular feedback (CTGF). We hypothesize that aldosterone sensitizes CTGF via a nongenomic mechanism that stimulates CNT ENaC via the aldosterone receptor GPR30. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing luminal NaCl in the CNT. During the control period, the concentration of NaCl that elicited a half-maximal response (EC50) was 37.0±2.0 mmol/L; addition of aldosterone 10-8 mol/L to the CNT lumen caused a left-shift (decrease) in EC50 to 19.3±1.3 mmol/L (P=0.001 vs. Control; n=6). Neither the transcription inhibitor actinomycin D (control EC50=34.7±1.9 mmol/L; aldosterone+actinomycin D EC50=22.6±1.6 mmol/L; n=6; P < 0.001) nor the translation inhibitor cycloheximide (control EC50=32.4±4.3 mmol/L; aldosterone+cycloheximide EC50=17.4±3.3 mmol/L; n=6; P < 0.001) prevented the effect of aldosterone. The aldosterone antagonist eplerenone prevented the sensitization of CTGF by aldosterone (control EC50=33.2±1.7 mmol/L; aldosterone+eplerenone EC50=33.5±1.3 mmol/L; n=7). The GPR30 receptor blocker G-36 blocked the sensitization of CTGF by aldosterone (aldosterone EC50=16.5±1.9 mmol/L; aldosterone+G-36 EC50=29.0±2.1 mmol/L; n=7; P < 0.001). Finally, we found that the sensitization of CTGF by aldosterone was mediated, at least in part, by the sodium/hydrogen exchanger (NHE). We conclude that aldosterone in the CNT lumen sensitizes CTGF via a nongenomic effect involving GPR30 receptors and NHE. Sensitized CTGF induced by aldosterone may contribute to renal damage by increasing Af-Art dilation and glomerular capillary pressure (glomerular barotrauma).
American journal of physiology. Renal physiology 06/2014; · 3.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Metformin is considered first-line treatment for type 2 diabetes mellitus. However, little is known about its effects in African American individuals. Objective: The objective of the study was to assess whether metformin's effect on glycemic control differs by race-ethnicity Design: Electronic health records were used to identify adults who had a diagnosis of diabetes, two or more fills of metformin, and two or more glycated hemoglobin (HbA1c) measurements. Pharmacy claims were used to estimate metformin exposure based on fill frequency and dose dispensed. Regression analyses modeled the relationship between metformin exposure and HbA1c levels. Analyses were stratified by race-ethnicity and baseline HbA1c values. Setting: The study was conducted at a large health system in southeast Michigan. Main Outcome Measure: Differences in HbA1c levels while on metformin were measured. Results: We identified 19ü672 patients with diabetes taking metformin; 7429 were African American and 8783 were European American. Baseline HbA1c values in these two groups were 7.81% (61.8 mmol/mol) and 7.38% (57.1 mmol/mol), respectively. Compared with no use, metformin was associated with a 0.62% (6.8 mmol/mol) reduction in HbA1c; however, there was a significant difference by race-ethnicity (P < .001). Among African American individuals, metformin use was associated with a 0.90% (9.8 mmol/mol) reduction in HbA1c levels, whereas among European Americans, metformin was associated with a 0.42% (4.6 mmol/mol) reduction. Irrespective of baseline HbA1c, metformin use was associated with lower HbA1c levels in African American individuals. Conclusions: African American individuals appear to have a better glycemic response to metformin when compared with European Americans. Further studies are needed to determine whether this translates to commensurate reductions in diabetes complications.
The Journal of clinical endocrinology and metabolism. 06/2014;
[Show abstract][Hide abstract] ABSTRACT: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been established as a mainstay of heart failure treatment. Current data are limited and conflicting regarding the consistency of ACE/ARB benefit across race groups in heart failure. This study aims to clarify this point.
Journal of cardiovascular medicine (Hagerstown, Md.). 05/2014;
[Show abstract][Hide abstract] ABSTRACT: Rising prescription opioid use and abuse have prompted widespread concern. However, to date there have been few rigorous investigations into the policies and events which may have contributed to these trends.
[Show abstract][Hide abstract] ABSTRACT: The activation of angiotensin II type 2 receptor (AT2R) has been considered cardioprotective. However, there are controversial findings regarding the role of overexpressing AT2R in the heart. Using transgenic mice with different levels of AT2R gene overexpression in the heart (1, 4, or 9 copies of the AT2R transgene: Tg(1), Tg(4), or Tg(9)), we studied the effect of AT2R overexpression on left ventricular remodeling and dysfunction post-myocardial infarction (MI). Tg(1), Tg(4), Tg(9), and their wild-type littermates were divided into (1) sham MI, (2) MI plus vehicle, and (3) MI plus AT2R antagonist. Treatments were started 4 weeks after MI and continued for 8 weeks. AT2R protein and mRNA expression in the heart was significantly increased in transgenic mice, and the increase positively correlated with copies of the transgene. AT1R protein and mRNA expression remained unchanged in Tg(1) and Tg(4) but slightly increased in Tg(9) mice. Systolic blood pressure and cardiac phenotypes did not differ among strains under basal conditions. MI caused myocardial hypertrophy, interstitial fibrosis, ventricular dilatation, and dysfunction associated with increased protein expression of Nox2 and transforming growth factor β1. These pathological responses were diminished in Tg(1) and Tg(4) mice. Moreover, the protective effects of AT2R were abolished by AT2R antagonist and also absent in Tg(9) mice. We thus conclude that whether overexpression of AT2R is beneficial or detrimental to the heart is largely dependent on expression levels and possibly via regulations of Nox2 and transforming growth factor β1 signaling pathways.
[Show abstract][Hide abstract] ABSTRACT: Our laboratory reported that male mice with cardiomyocyte-selective knockout of the prostaglandin E2 EP4 receptor sub-type (EP4 KO) exhibit reduced cardiac function. Gene array on left ventricles (LV) showed increased fractalkine, a chemokine implicated in heart failure. We therefore hypothesized that fractalkine is regulated by PGE2 and contributes to depressed contractility via alterations in intracellular calcium.
Fractalkine was measured in LV of 28-32 week old male EP4 KO and wild type controls (WT) by ELISA and the effect of PGE2 on fractalkine secretion was measured in cultured neonatal cardiomyocytes and fibroblasts. The effect of fractalkine on contractility and intracellular calcium was determined in Fura-2 AM-loaded, electrical field-paced cardiomyocytes. Cardiomyocytes (AVM) from male C57Bl/6 mice were treated with fractalkine and responses measured under basal conditions and after isoproterenol (Iso) stimulation.
LV fractalkine was increased in EP4 KO mice but surprisingly, PGE2 regulated fractalkine secretion only in fibroblasts. Fractalkine treatment of AVM decreased both the speed of contraction and relaxation under basal conditions and after Iso stimulation. Despite reducing contractility after Iso stimulation, fractalkine increased the Ca(2+) transient amplitude but decreased phosphorylation of cardiac troponin I, suggesting direct effects on the contractile machinery.
Fractalkine depresses myocyte contractility by mechanisms downstream of intracellular calcium.
PLoS ONE 09/2013; 8(7):e69832. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Nonadherence to inhaled corticosteroids (ICSs) for asthma maintenance therapy is common and is associated with poor asthma outcomes. Simplifying dosing regimens for some chronic disease conditions has resulted in better adherence; however, little is known regarding the effect of ICS dosing on adherence for the treatment of asthma.
To determine whether once daily dosing is associated with higher adherence to ICS therapy when compared with 2 or more times daily dosing among patients with asthma.
Six years of pharmacy claims data were linked with prescription information to estimate ICS therapy adherence for patients with asthma 12 to 56 years of age who were members of a large health maintenance organization. Patient follow-up continued from the initial ICS fill until one of the following: the last ICS fill in the observation period, a switch of ICS dosing regimen, or the initiation of ICS and long-acting β-agonist combination therapy. Adherence was estimated by calculating a continuous multiple-interval measure of medication availability. Regression models were used to assess the relationship between adherence in patients treated with once daily vs 2 or more times daily ICS therapy.
Among the 1,302 patients who met the inclusion criteria, 17% were prescribed once daily therapy, and 83% were prescribed 2 or more times daily therapy. Models comparing ICS adherence among individuals following once daily and 2 or more times daily ICS regimens suggested that once daily dosing was associated with an approximately 20% increase in adherence. This significant difference persisted among subgroups defined by sex, race/ethnicity, age, and asthma severity.
Once daily dosing was associated with higher adherence to ICS therapy; this included clinically relevant subgroups.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 09/2013; 111(3):216-20. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retention of study participants in randomized controlled trials (RCTs) is crucial to study validity.
We analyzed the results of four retention strategies used to reconnect with urban teens enrolled in a school-based RCT and overdue for a 12-month follow-up survey.
Traditional retention strategies used to reconnect with teens categorized as 'unable to contact' were weekly redials of nonworking telephone numbers and mailings to the student's home. Nontraditional retention strategies were obtaining assistance from school administration and performing outreach on Facebook.
Of the 422 students enrolled, 125 (29.5%) were overdue for a 12-month follow-up survey, but had no working telephone number (unable to contact). We made 196 attempts to contact these 125 students, of which 82 attempts (41.8%) were successful in 'reconnecting' with the student. Using 'mailed reminder letters' as the referent category, odds ratios (95% confidence intervals) for the association between the strategy used and reconnecting were 4.60 (1.8-11.8), 1.94 (1.01-3.73), and 2.91 (0.58-14.50), respectively, for telephone number redials, Facebook outreach, and school administration assistance. Of the 422 students, 380 (90%) ultimately completed the 12-month follow-up survey.
Retention strategies were not applied hierarchically or systematically. We were unable to determine student preference for a particular strategy. Findings are likely only applicable to similar study populations.
A mix of traditional retention strategies and more contemporary methods was effective in reconnecting with urban teenagers enrolled in a school-based RCT and in controlling attrition during the 12-month follow-up survey period.
[Show abstract][Hide abstract] ABSTRACT: Myocardial matrix turnover involves a dynamic balance between collagen synthesis and degradation, which is regulated by matrix metalloproteinases (MMPs). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) is a small peptide that inhibits cardiac inflammation and fibrosis. However, its role in MMP regulation is not known. Thus, we hypothesized that Ac-SDKP promotes MMP activation in cardiac fibroblasts and decreases collagen deposition via this mechanism. To that end, we tested the effects of Ac-SDKP on interleukin-1β (IL-1β; 5 ng/ml)-stimulated adult rat cardiac fibroblasts. We measured total collagenase activity, MMP-2, MMP-9, and MMP-13 expressions, and activity along with their inhibitors, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. In order to examine the effects of Ac-SDKP on the signaling pathway that controls MMP transcription, we also measured nuclear factor-κB (NFκB) and p42/44 mitogen-activated protein kinase (MAPK) activation. Ac-SDKP did not alter collagenase or gelatinase activity in cardiac fibroblasts under basal conditions, but blunted the IL-1β-induced increase in total collagenase activity. Similarly, Ac-SDKP normalized the IL-1β-mediated increase in MMP-2 and MMP-9 activities and MMP-13 expression. Inhibition of MMPs by Ac-SDKP was associated with increased TIMP-1 and TIMP-2 expressions. Collagen production was not affected by Ac-SDKP, IL-1β, or a combination of both agents. Ac-SDKP blocked IL-1β-induced p42/44 phosphorylation and NFκB activation in cardiac fibroblasts. We concluded that the Ac-SDKP-inhibited collagenase expression and activation was associated with increased expression of TIMP-1 and TIMP-2. These pharmacological effects of Ac-SDKP may be linked to the inhibition of MAPK and NFκB pathway.
Pflügers Archiv - European Journal of Physiology 05/2013; · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Although depression has been linked with asthma, its relationship with asthma exacerbations, including emergency department (ED) visits and oral steroid (OS) use, has not been well documented. The aim is to investigate whether depression increases exacerbations among patients with asthma.Method
The study included 568 participants with asthma who were between 18 and 56 years old, were taking an inhaled corticosteroid, and participated in baseline and follow-up surveys. Surveys and medical records from a large, health system were collected as part of the Adherence Feedback for Improving Respiratory Medication Use trial. Number of ED visits and OS prescription fills for asthma were calculated for 12-month periods before and after the follow-up survey. Depression was measured using a standardized two-item instrument. Negative binomial regression and modified proportional hazards models were used.ResultsAmong patients with asthma, those who had depression (n = 187; 32.9%) were at increased risk for an asthma-related ED visit (adjusted relative risk = 1.96, 95% confidence interval [CI] = 1.02-3.75), but not an OS fill (adjusted relative risk = 0.98; 95% CI = 0.72-1.32). Participants with depression and asthma who received psychiatric treatment via antidepressant medication (n = 126; 22.2%) or psychotherapy (n = 39; 6.9%) were more likely to have an ED visit (medication hazard ratio = 2.09, 95% CI = 1.35-3.25; psychotherapy hazard ratio = 2.07, 95% CI = 1.38-3.22).Conclusions
This study suggests a temporal relationship between depression and asthma-related ED visits. Research and practice must consider the importance of these comorbid conditions.Trial RegistrationClinicalTrials.gov identifier: NCT00459368.
Psychosomatic Medicine 02/2013; · 4.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to compare the benefit of beta-blockers (BB) in heart failure (HF) with preserved versus reduced ejection fraction (EF).
This was a retrospective study of insured patients who were hospitalized for HF from January 2000 to June 2008. Pharmacy claims were used to estimate BB exposure over 6-month rolling windows. The association between BB exposure and all-cause hospitalization or death was tested with the use of time-updated proportional hazards regression, with adjustment for baseline covariates and other HF medication exposure. The groups were compared by stratification (EF <50% vs ≥50%) and with the use of an EF-group × BB exposure interaction term. A total of 1,835 patients met the inclusion criteria, 741 (40%) with a preserved EF. Median follow-up was 2.1 years. In a fully adjusted multivariable model, BB exposure was associated with a decreased risk of death or hospitalization in both groups (EF <50%: hazard ratio [HR] 0.53 [P < .0001]; EF ≥50%: HR 0.68 [P = .009]). There was no significant difference in this protective association between groups (interaction: P = .32).
BB exposure was associated with a similar protective effect regarding time to death or hospitalization in HF patients regardless of whether EF was preserved or reduced. An adequately powered randomized trial of BB in HF with preserved EF is warranted.
Journal of cardiac failure 02/2013; 19(2):73-9. · 3.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Medication adherence is an important determinant of disease outcomes, yet medication use on average tends to be low among patients with chronic conditions, including asthma. Although several predictors of non-adherence have been assessed, more research is needed on patients' beliefs about God and how these relate to medication use.
To examine the relationship between perceptions about "God's" role in health and other locus of control factors with inhaled corticosteroid (ICS) adherence among asthma patients.
Participants were from a clinical trial to improve ICS adherence and were 5-56 years old, had a diagnosis of asthma, and were receiving ICS medication. Baseline adherence was estimated from electronic prescription and pharmacy fill records. Patients were considered to be adherent if ICS use was ≥80% of prescribed. A baseline survey with the Multidimensional Health Locus of Control scale was used to assess five sources (God, doctors, other people, chance, and internal).
Medication adherence was low (36%). Patients' who had a stronger belief that God determined asthma control were less likely to be adherent (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.70-0.96). This relationship was stronger among African American (OR 0.68, 95% CI0.47-0.99) compared to white patients (OR 0.89, 95% CI 0.75-1.04), and among adults (OR 0.81, 95% CI 0.69-0.96) compared to children (OR 0.84, 95% CI 0.58-1.22).
Patients' belief in God's control of health appears to be a factor in asthma controller use, and therefore should be considered in physician-patient discussions concerning course of treatment.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 02/2013; 110(2):75-79.e2. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: There are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American subjects are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care or whether there is a predisposing genetic component. OBJECTIVE: We sought to assess the relationship between genetic ancestry and severe exacerbations among African American subjects with asthma. METHODS: Participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These subjects were 12 to 56 years of age, received care from a single large health system, and had a physician's diagnosis of asthma. Genetic ancestry was estimated by using a set of validated ancestry informative markers. Severe exacerbations (ie, asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims. RESULTS: We assessed genetic ancestry in 392 African American subjects with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among male but not female subjects. The association among male subjects persisted after adjusting for potential confounders (relative rate, 4.30 for every 20% increase in African ancestry; P = .029). CONCLUSIONS: African ancestry was significantly and positively associated with severe exacerbations among male African American subjects. These findings suggest that a portion of the risk of asthma exacerbations in this high-risk group is attributable to a genetic risk factor that partitions with ancestry.
The Journal of allergy and clinical immunology 10/2012; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-Acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits endothelin-1 (ET-1)-induced activation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) and collagen production in cultured rat cardiac fibroblasts (RCFs). However, we do not know whether its inhibitory effect on p44/42 MAPK is due to the altered activity of protein tyrosine phosphatases (PTPs), which in turn downregulate the p44/42 MAPK signaling pathway. The activity of Src homology 2-containing protein tyrosine phosphatase-2 (SHP-2) is downregulated by ET-1 in RCFs; thus, we hypothesized that Ac-SDKP inhibits ET-1-stimulated collagen production in part by preserving SHP-2 activity and thereby inhibiting p44/42 MAPK phosphorylation. When we stimulated RCFs with ET-1 in the presence or absence of Ac-SDKP, we found that (a) PTP activity was reduced by ET-1 and (b) this effect was counteracted by Ac-SDKP in a dose-dependent fashion. Next, we extracted SHP-2 from RCF lysates by immunoprecipitation and determined that (a) ET-1 inhibited SHP-2 by 40 % and (b) this effect was prevented by Ac-SDKP. However, Ac-SDKP failed to inhibit ET-1-induced p44/42 MAPK phosphorylation in RCFs treated with SHP-2 short hairpin RNA (shRNA); in contrast, in cells transfected with control shRNA, Ac-SDKP's inhibitory effect on ET-1-induced p44/42 MAPK activation remained intact. Moreover, the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production was blunted in cells treated with the SHP-1/2 inhibitor NSC-87877. Thus, we concluded that the inhibitory effect of Ac-SDKP on ET-1-stimulated collagen production by RCFs is mediated in part by preserving SHP-2 activity and thereby preventing p44/42 MAPK activation. Ac-SDKP or its analogs could represent a new therapeutic tool to treat fibrotic diseases in the cardiovascular system.
Pflügers Archiv - European Journal of Physiology 09/2012; 464(4):415-23. · 4.87 Impact Factor