Transforming growth factor beta1 and aldosterone

It is well established that blocking renin-angiotensin II-aldosterone system (RAAS) is effective for the treatment of cardiovascular and renal complications in hypertension and diabetes mellitus. Although the induction of transforming growth factor beta1 (TGFbeta1) by components of RAAS mediates the hypertrophic and fibrogenic changes in cardiovascular-renal complications, it is still controversial as to whether TGFbeta1 can be a target to prevent such complications. Here we review recent findings on the role of TGFbeta1 in fluid homeostasis, focusing on the relationship with aldosterone

Identification of Aortic Arch-Specific Quantitative Trait Loci for Atherosclerosis by an Intercross of DBA/2J and 129S6 Apolipoprotein E-Deficient Mice

<div><p>The genetic background of apolipoprotein E (apoE) deficient mice influences atherosclerotic plaque development. We previously reported three quantitative trait loci (QTL), <i>Aath1–Aath3</i>, that affect aortic arch atherosclerosis independently of those in the aortic root in a cross between C57BL6 apoEKO mice (B6-apoE) and 129S6 apoEKO mice (129-apoE). To gain further insight into genetic factors that influence atherosclerosis at different vascular locations, we analyzed 335 F2 mice from an intercross between 129-apoE and apoEKO mice on a DBA/2J genetic background (DBA-apoE). The extent of atherosclerosis in the aortic arch was very similar in the two parental strains. Nevertheless, a genome-wide scan identified two significant QTL for plaque size in the aortic arch: <i>Aath4</i> on Chromosome (Chr) 2 at 137 Mb and <i>Aath5</i> on Chr 10 at 51 Mb. The DBA alleles of <i>Aath4</i> and <i>Aath5</i> respectively confer susceptibility and resistance to aortic arch atherosclerosis over 129 alleles. Both QTL are also independent of those affecting plaque size at the aortic root. Genome analysis suggests that athero-susceptibility of <i>Aath4</i> in DBA may be contributed by multiple genes, including <i>Mertk</i> and <i>Cd93</i>, that play roles in phagocytosis of apoptotic cells and modulate inflammation. A candidate gene for <i>Aath5</i> is <i>Stab2</i>, the DBA allele of which is associated with 10 times higher plasma hyaluronan than the 129 allele. Overall, our identification of two new QTL that affect atherosclerosis in an aortic arch-specific manner further supports the involvement of distinct pathological processes at different vascular locations.</p></div

Haplotype comparison.

<p>Chromosome maps of <i>Aath4</i> on Chr 2 (A) and <i>Aath5</i> on Chr 10 (B) from UNC Mouse Phylogeny Viewer. 129 sequences and B6/DBA regions identical to 129 are shown in green; B6 sequences different from 129, and DBA sequences identical to B6 but not to 129 are shown in purple; DBA-specific sequences are shown in orange. Arrows below indicate the position of representative candidate genes. Homologous human chromosomal regions are derived from the Virtual Comparative Map (VCMap) tool. Human disease-associated regions are indicated above the human chromosomal regions.</p

DBA-allele dependent upregulation of Stab2 and its ligand hyaluronan.

<p>(A) Plasma hyaluronan concentrations in the wild-type male C57BL/6, 129S6 and DBA2/J mice. Box-and-whisker plots: midline, median; box, 25th and 75th percentiles; whiskers, 1.5× interquartile range; dots, outliers. Numbers of mice were indicated below the plots. (B) Plasma hyaluronan concentrations in a subset of F2 males and females of 129-apoE × DBA-apoE. Mice were grouped by the genotype of rs13480630 on Chr 10, which is located near <i>Stab2</i>. Differences were compared by Kruskal–Wallis test followed by Steel-Dwass test for (A) and (B). (C) Effects of other hyaluronan metabolic loci on plasma hyaluronan concentrations. The same set of F2 population was grouped into 129-homo, Hetero and DBA-homo according to the genotype of rs13459148 on Chr 17 (near <i>Has1</i>), rs13482628 on Chr 15 (near <i>Has2</i>), rs3667255 on Chr 8 (near <i>Has3</i>), rs13480325 on Chr 9 (near <i>Hayl1–3</i>), rs13476631 on Chr 2 (near <i>Cd44</i>), rs13479497 on Chr 7 (near <i>Lyve1</i>) and rs13480973 on Chr 11 (near <i>Hmmr</i>). Kruskal–Wallis test was used for the multiple comparison. (D) Expression levels of Stab2 in various tissues from B6 (black filled bars), 129 (gray filled bars) and DBA (open bars). Data are relative to those in the B6 liver (= 100) assessed by quantitative RT-PCR. ^**<i>P</i> < 0.01, ^***<i>P</i> < 0.001 vs. B6; ^##<i>P</i> < 0.01, ^###<i>P</i> < 0.001 vs. 129 (one-way ANOVA followed by Tukey-Kramer’s HSD test). Data were shown as the mean ± SD. Sample numbers were indicated in the bars.</p

QTL for atherosclerosis at the aortic arch identified by genome-wide single scan.

<p>QTL for atherosclerosis at the aortic arch identified by genome-wide single scan.</p

Allelic effects of QTL for atherosclerosis.

<p>Allelic distributions of the main effect QTL for arch plaques at the nearest makers to the peaks in Chr 2 and Chr 10. Atherosclerotic plaque size is indicated in square root (sqrt). Data represent the mean ± SD.</p