Showing papers by "Hans Ackerman published in 2022"

Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice

Abstract: Angiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, change tissue levels of ACE2 in healthy male and female mice. Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. ACE2 protein index (ACE2 protein / total protein) was determined on small intestine, lung, kidney, and brain. Oral lisinopril increased ACE2 protein index across all tissues (p < 0.0001 vs control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs control). Tissue ACE2 remained elevated in mice 21 days after cessation of lisinopril (p = 0.02). Across both cohorts, plasma ACE2 did not correlate with ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in males than females (p < 0.0001). Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.

Alpha Globin Gene Copy Number Is Associated with Prevalent Chronic Kidney Disease and Incident End-Stage Kidney Disease among Black Americans

Abstract: Visual Abstract Export Background α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic–mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. Methods Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. Results Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P<0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P=0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P=0.005). Conclusions Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.

Alpha globin gene copy number and hypertension risk among Black Americans

Abstract: BACKGROUND: Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. METHODS: Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure [≥] 140mmHg or diastolic blood pressure [≥] 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. RESULTS: Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07). CONCLUSIONS: There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.

Alpha Globin Gene Copy Number and Exhaled Nitric Oxide in Healthy Black Adults

Abstract: BACKGROUND: Nitric oxide has a range of biological activity in the lung and the fractional exhalation of nitric oxide (FeNO) is useful in patients with asthma in whom treatment is being considered. Normal variation in FeNO may impact the interpretation of this physiologic measurement, yet little is known about genetic factors that influence FeNO, particularly among Black populations. Growing evidence that globins are co-expressed with NOS in airway epithelium, along with the structural similarity of iNOS and eNOS, imply that globins may regulate NO signaling not only in the vascular endothelium, but in the airway epithelium as well. Given that Black individuals have increased HBA allele count variation, we assessed the role of alpha globin in airway nitric oxide physiology, we examined the association of alpha globin gene deletions with FeNO in healthy Black individuals. METHODS: We measured HBA copy number via droplet digital PCR in Black healthy volunteers age 18-40 years were enrolled in a multi-center, cross-sectional cohort from 4 sites near Durham, North Carolina. Subjects self-reported health status, age, sex, race, and ethnicity. Only non-Hispanic African American subjects were enrolled in the original study. Exclusion criteria for this analysis were: 1) not consenting to future research and 2) serum cotinine level >25 ng/mL to exclude active tobacco use. For continuous measures, medians and 25th and 75th percentiles were calculated by alpha globin genotype. Differences between groups were assessed by Kruskal-Wallis test. Categorical variables were assessed by Fisher's exact test. IgE and FeNO were log transformed due to skewness. The association of HBA copy number with FeNO was evaluated using multivariable linear regression employing a linear effect of HBA allele count (2-5 HBA copies). RESULTS: Among DNA specimens from 643 Black individuals, HBA genotype frequencies were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa, and 8 (1.2%) aa/aaa, with the median (25th, 75th percentile) measured FeNO value of 20 (13, 31) ppb. Subjects were 35% male with median age 20 (19, 22) years and median IgE level of 58 (22, 160) kU/L. After adjustment for sex, age, and log transformed total IgE, the coefficient for HBA copy number with FeNO was -0.005 (95% CI: -0.042, 0.033, p=0.81). CONCLUSIONS: No clear association between HBA copy number and FeNO was found among healthy Black adults in this cohort. Many questions regarding the roles of alpha and beta globin in epithelial NO signaling and pulmonary pathophysiology remain unanswered.

Alpha globin gene copy number and hypertension risk among Black Americans

Abstract: BACKGROUND: Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. METHODS: Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. RESULTS: Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07). CONCLUSIONS: There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.