Female-Specific Hypertension Loci on Rat Chromosome 13

Hoffman, Matthew J.; Flister, Michael J.; Núñez, Lizbeth; Xiao, Bing; Greene, Andrew S.; Jacob, Howard J.; Moreno, Carol

doi:10.1161/hypertensionaha.113.01708

Cited by 16 publications

(13 citation statements)

References 64 publications

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“…Fluorescence microscopy experiments confirmed that the Mas1 receptor antibody (Santa Cruz, sc-135063) epitope was intracellular (Supplemental Figure I). Signaling complexes were then verified for presence of Mas1 by immunoblot (Figure 2B, Supplemental Figure II) according to previous protocols 22–25 using rabbit anti-rat Mas1 primary antibody (Santa Cruz, sc-135063) at 1:1000 and secondary HRP-conjugated goat anti-rabbit IgG antibody (BioRad) at 1:2000, as well as in the raw MS/MS data (Supplemental Figure II). In the Ang-(1-7) stimulated RMVEC signaling complexes, 50 proteins were identified as significantly increased (p<0.05, n=8 plus a technical replicate, 16 total MS runs) versus non-stimulated RMVECs after application of stringent filters (Figure 2C, Table 1, Supplemental Table I).…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Stodola

Wagner

Didier

et al. 2017

ATVB

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Objective Angiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1 (AT1R). Angiotensin 1-7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, while the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7). Approach and Results This study shows that low dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similarly to a low, subpressor dose of AngII acting through AT1R. Additionally, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Utilizing proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho Family GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen activated protein kinase (MAPK), and extracellular signal-related kinase (ERK) signaling. Further experimental antagonism of ERK1/2 and p38MAPK signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7). Conclusions These results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII as compared to the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AT1R signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of MAPK/ERK signaling in maintaining vascular function.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Stodola

Wagner

Didier

et al. 2017

ATVB

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“…Within the region, it is also possible that other nonsynonymous variants and intergenic variants have functional consequences beyond the limitations of prediction software. Thus, validating these candidates genes will likely require further narrowing of the QTL by congenics (26, 50, 51), gene expression analysis, and/or directly testing candidates by gene-editing (20, 52, 53), all of which we have done previously for other disease loci (see below for description).…”

Section: Discussionmentioning

confidence: 99%

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

et al. 2014

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The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that impact only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the non-malignant microenvironment. Using CXM, we defined genetic variant(s) on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3IL2Rγ consomic model compared to the SSIL2Rγ parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3IL2Rγ background. Through comparative mapping and whole genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment which underlie differences in breast cancer risk.

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“…29 It is also possible that multiple causative variants co-segregate at the 830 kb locus, as we have demonstrated previously for other hypertension loci. 15, 23, 30 However, future studies targeting specific genes or further reducing the congenic interval will be necessary to localize the causative variant(s).…”

Section: Discussionmentioning

confidence: 99%

Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

et al. 2014

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Previously, we found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12BN background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 vs. 144±2 mmHg; P<0.001). Using congenic mapping, we have now narrowed the blood pressure locus by 86% from a 6.1 Mb region containing 133 genes to an 830 kb region (chr12:14.36-15.19 Mb) with 14 genes. Compared with the SS-12BN consomic, the 830 kb blood pressure locus was associated with a Δ+15 mmHg (P<0.01) increase in blood pressure, which coincided with elevated albuminuria (Δ+32 mg/day; P<0.001), proteinuria (Δ+48 mg/day; P<0.01), protein casting (Δ+154%; P<0.05), and renal fibrosis (Δ+79%; P<0.05). Of the 14 genes residing in the 830 kb locus, 8 were differentially expressed and among these, Chst12 (carbohydrate chondroitin 4 sulfotransferase 12) was the most consistently down-regulated by 2.6 to 4.5-fold (P<0.05) in both the renal medulla and cortex under normotensive and hypertensive conditions. Moreover, whole genome sequence analysis of overlapping blood pressure loci revealed an ∼86 kb region (chr12:14,541,567-14,627,442 bp) containing single nucleotide variants near Chst12 that are unique to the hypertensive SS strain when compared to the normotensive BN, SR, and WKY strains. Finally, the 830 kb interval is syntenic to a region on human chromosome 7 that has been genetically linked to blood pressure, suggesting that insight gained from our SS-12BN congenic strain may be translated to a better understanding of human hypertension.

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Female-Specific Hypertension Loci on Rat Chromosome 13

Cited by 16 publications

References 64 publications

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

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