This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major objective of this project is to characterize the abnormalities of vascular gene expression occurring in early, subclinical stages of vascular disease, as assessed by large artery function, in adult obesity and to assess its correlates and the potential pathobiological mediating pathways between vascular dysfunction and vascular gene expression. While compelling evidence indicates that genetic and other biological factors predispose to obesity and hypertension, these common, co-occurring disorders likely reflect a complex interplay between biological factors and the psychosocial and cultural environment. Taken together, this series of studies will be among the first to link changes in human vascular mRNA expression profiles with physiologic alterations in vascular function and obesity. Overall, it is anticipated that these experiments will provide new insights into the molecular basis of vascular stiffness and endothelial dysfunction in high-risk African-American obese subjects.
The specific aims were: 1. To determine whether vasculopathic gene expression is up-regulated and vasculoprotective gene expression is down-regulated in presence of arterial stiffness, as defined by the upper quartile of the vascular function distribution. These abnormalities would thus create a deleterious imbalance of vasculopathic: vasculoprotective gene expression in subjects with vascular dysfunction relative to those without. Furthermore, we hypothesize that this imbalance will be greater in obese than in lean individuals. Our model predicts that activation of Angiotensin (Ang) II and aldosterone combined with decreased activity of nitric oxide (NO) and PPAR-? will induce changes in vascular mRNA expression that promote vascular remodeling and vascular stiffness. Although there are many candidate genes, we will focus on genes that: 1) characterize the activity of the Renin Angiotensin Aldosterone System (RAAS), nitric oxide (NO), and peroxisome proliferators-activated receptor (PPAR) ? signaling pathways, 2) influence vascular tone and 3) influence distensibility. Overall, it is anticipated that these experiments will provide new insights into the molecular basis of vascular stiffness and endothelial dysfunction in high-risk African-American obese subjects. 2. To determine whether insulin-resistance, oxidative stress, and inflammation mediate or modulate the association of interest. In case of mediation, the effect of obesity on vascular function and vascular gene expression will be explained away partially or totally by these biomarkers. In case of modulation, the presence of these factors will markedly increase the vascular dysfunction and the gene expression imbalance observed in obese individuals. 3. To assess the effect of sodium intake manipulation on vascular function and gene expression: (a) high intake of sodium will lead to increased blood pressure, greater arterial stiffness, and imbalance of the vasculopathic:vasculoprotective gene expression in favor of the former, whereas low sodium diet will lead to the opposite effect and the net result will be a BP reduction;(b) the high-low gradient in vascular dysfunction and imbalance of gene expression will be greater in obese than in lean people. To address this aim, the original design was as follows: The design for the proposed 3-year study is a cross-sectional study followed by a cross-over, two-period, double-blind randomized trial. + The cross-sectional stage will recruit 110 adult African Americans residing in the Atlanta area stratified by anthropometric status as defined by body-mass-index (BMI): Lean (BMI 25 kg/m2) and obese (BMI e30 kg/m2). Within each stratum, the gender ratio will be 1:1. This sample size was calculated based on the literature of vascular dysfunction in obese. + At the end of the recruitment, each group will be categorized based on the quartile distribution of vascular function. Obese in the fourth quartile of vascular function and lean in the first quartile will undergo gluteal biopsy. The rationale for choosing this design stems from our experience in the pilot study. Despite the large difference in BMI between the obese and lean enrolled in the pilot study (37.3 ? 1.5 kg/m2 vs. 22.2 ? 1.5 kg/m2, p0.0001), the overall distribution of vascular function for obese was not quite different from that of lean, though those in the highest quartile for systemic resistance, and the lowest quartile for arterial compliance, i.e., those with stiffest arteries, were obese (borderline p=0.07). Another reason why we did not observe any difference in vascular function between obese and lean may be the small sample size (total n=14) or the relatively healthy status of the obese enrolled in the study. Because we are interested in vascular gene expression associated with vascular dysfunction, the proposed design is the most appropriate. To speed up the recruitment process we will invite the people in the CRC database who have enrolled in the endothelial function study and those who are through with the vascular function study (see details in study population section). The reason why gluteal biopsy is performed on the selected quartiles is because epidemiological studies show that the relative risk of developing hypertension for normotensive people is statistically significantly greater for those in the 4th quartile of the distribution of arterial stiffness compared to those in the first quartile,12 whereas the risk for hypertensives to develop an end-organ-damage first event in relation to aortic stiffness appears to be graded for coronary heart disease,16 stroke,16,17 and renal dysfunction.13,18 + Cross-over randomized trial with sodium intake manipulation will be the last step. It encompasses feeding and free-living components. Because gluteal biopsy is not a simple test, we opted to minimize the risk of misclassification attached to sodium intake and measurement by conducting controlled fed interventions in the subgroup with biopsy (n ~ 30).
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