Transforming growth factor-beta 1 hyperexpression in African-American hypertensives: A novel mediator of hypertension and/or target organ damage

Abstract

Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-beta(1) (TGF-beta(1)) is hyperexpressed in hypertensives compared with normotensives and that TGF-beta(1) overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-beta(1) is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-beta(1), which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-beta(1) is produced in excess. TGF-beta(1) profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-beta(1) protein levels are highest in black hypertensives, and TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro(10)) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-beta(1) mRNA and protein. Our findings support the idea that TGF-beta(1) hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.

Figure 1

Design, location, and sequences of the oligonucleotide primers for the detection of codon 10 polymorphisms by ARMS-PCR. A penultimate mismatch was introduced into the sense (common) primer as well as into the allele-specific antisense ARMS primers.

Figure 2

Serum TGF-β₁ protein levels. Circulating levels of TGF-β₁ protein were quantified by using a TGF-β₁-specific sandwich ELISA. TGF-β₁ protein levels, distinguished by diagnosis (hypertensive vs. normotensive) are shown in A. The mean ± SEM TGF-β₁ level was 188 ± 7 ng/ml in normotensives (N) and was 261 ± 9 ng/ml in hypertensives (HT). TGF-β₁ protein levels, distinguished by diagnosis as well as by race, are illustrated in B. The mean ± SEM TGF-β₁ concentrations were 165 ± 6 ng/ml, 221 ± 12 ng/ml, 235 ng/ml, and 322 ng/ml in normotensive whites (NW), normotensive blacks (NB), hypertensive whites (HTW), and hypertensive blacks (HTB), respectively (P < 0.0001, ANOVA). The frequency distribution of TGF-β₁ levels, distinguished by race and diagnosis, is shown in C.

Figure 3

TGF-β₁ mRNA steady-state levels in hypertensives and normotensives. The mean ± SEM TGF-β₁ mRNA/GAPDH mRNA ratios, calculated after quantification of mRNA levels in PBMC, were 3.35 ± 0.81 and 4.51 ± 0.69 in normotensives (N) and hypertensives (HT), respectively (P < 0.04, Mann–Whitney two-sample test).