Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis

Tsou, Chia-Yuan; Chen, C.-Y.; Zhao, Jin; Su, Kuo‐Hui; Lee, H.-T.; Song, Lin; Shyue, Song Kun; Hsiao, Sheng Huang; Lee, T.-S.

doi:10.1111/apha.12210

Cited by 31 publications

(36 citation statements)

References 46 publications

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“…Third, a recently published paper suggests that complete knockout of Gucy1a3 in mice may reduce atherosclerotic plaque formation on a proatherogenic background ( Ldlr −/− ) 37 . In contrast to this study, we and others investigated a partial loss of sGC activity and showed experimentally in mice and functionally in human materials that this leads to increased disease risk 10,38–40 . Thus, in the total Gucy1a3 knockout model compensatory mechanisms affecting NO/cGMP signaling, including a marked compensatory increase of Gucy1a2 expression in Gucy1a3 −/− VSMC 37 , may not have been adequately addressed.…”

Section: Discussionmentioning

confidence: 66%

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

et al. 2017

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Background A chromosomal locus at 4q32.1 has been genome-wide significantly associated with coronary artery disease risk. The locus encompasses GUCY1A3, which encodes the α1-subunit of the soluble guanylyl cyclase (sGC), a key enzyme in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway. The mechanism linking common variants in this region with coronary risk is not known. Methods Gene and protein expression were analyzed using quantitative polymerase chain reaction (qPCR) and immunoblotting, respectively. Putative allele-specific transcription factors were identified using in silico analyses and validated via allele-specific quantification of antibody-precipitated chromatin fractions. Regulatory properties of the lead risk variant region were analyzed using reporter gene assays. To assess the effect of ZEB1, siRNA-mediated knockdown as well as overexpression experiments were performed. Association of GUCY1A3 genotype and cellular phenotypes were analyzed using vascular smooth muscle cell (VSMC) migration assays and platelet aggregation analyses. Results Whole blood GUCY1A3 mRNA levels were significantly lower in individuals homozygous for the lead (rs7692387) risk variant. Likewise, reporter gene assays demonstrated significantly lower GUCY1A3 promoter activity for constructs carrying this allele. In silico analyses located a DNase I hypersensitivity site to rs7692387 and predicted binding of the transcription factor ZEB1 rather to the non-risk allele, which was confirmed experimentally. Knockdown of ZEB1 resulted in more profound reduction of non-risk allele promoter activity, as well as a significant reduction of endogenous GUCY1A3 expression. Ex vivo studied platelets from homozygous non-risk allele carriers displayed enhanced inhibition of adenosine diphosphate-induced platelet aggregation by the NO donor sodium nitroprusside and the phosphodiesterase 5 inhibitor sildenafil as compared to homozygous risk allele carriers. Moreover, pharmacologic stimulation of sGC led to reduced migration only in VSMC homozygous for the non-risk allele. In the Hybrid Mouse Diversity Panel higher levels of GUCY1A3 expression correlated with less atherosclerosis in the aorta. Conclusions Rs7692387 is located in an intronic site that modulates GUCY1A3 promoter activity. The transcription factor ZEB1 binds preferentially to the non-risk allele leading to an increase in GUCY1A3 expression, higher sGC levels, and higher sGC activity after stimulation. Finally, human and mouse data link augmented sGC expression to lower risk of atherosclerosis.

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Section: Discussionmentioning

confidence: 66%

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

et al. 2017

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“…[16][17][18] Increase in ABCA1 expression in macrophages promotes cholesterol efflux and decreases cholesterol accumulation of foam cells, thereby retarding the progression of atherosclerosis. [33][34][35] For instance, overexpression of human ABCA1 in Apoe −/− mice increases cholesterol efflux from macrophages and slows down the progression of atherosclerosis. 36 Our current findings further con- PT activity and is associated with hyperlipidemia and calcification in CAD patients.…”

Section: Discussionmentioning

confidence: 99%

The phosphatase activity of soluble epoxide hydrolase regulates ATP‐binding cassette transporter‐A1‐dependent cholesterol efflux

Lien

Chen

Lee

et al. 2019

J Cellular Molecular Medi

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The contribution of soluble epoxide hydrolase (sEH) to atherosclerosis has been well defined. However, less is understood about the role of sEH and its underlying mechanism in the cholesterol metabolism of macrophages. The expression of sEH protein was increased in atherosclerotic aortas of apolipoprotein E‐deficient mice, primarily in macrophage foam cells. Oxidized low‐density lipoprotein (oxLDL) increased sEH expression in macrophages. Genetic deletion of sEH (sEH−/−) in macrophages markedly exacerbated oxLDL‐induced lipid accumulation and decreased the expression of ATP‐binding cassette transporters‐A1 (ABCA1) and apolipoprotein AI‐dependent cholesterol efflux following oxLDL treatment. The down‐regulation of ABCA1 in sEH−/− macrophages was due to an increase in the turnover rate of ABCA1 protein but not in mRNA transcription. Inhibition of phosphatase activity, but not hydrolase activity, of sEH decreased ABCA1 expression and cholesterol efflux following oxLDL challenge, which resulted in increased cholesterol accumulation. Additionally, oxLDL increased the phosphatase activity, promoted the sEH‐ABCA1 complex formation and decreased the phosphorylated level of ABCA1 at threonine residues. Overexpression of phosphatase domain of sEH abrogated the oxLDL‐induced ABCA1 phosphorylation and further increased ABCA1 expression and cholesterol efflux, leading to the attenuation of oxLDL‐induced cholesterol accumulation. Our findings suggest that the phosphatase domain of sEH plays a crucial role in the cholesterol metabolism of macrophages.

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“…On the other hand, activation of sGC seems to be rather protective as enhancing cGMP formation reduces the expression of adhesion molecules and leukocyte recruitment [2]. It has also been reported that the activation of the sGC prevents formation of foam cells and reduces atherosclerotic lesions in ApoE -/-mice [28]. Sovershaev et al further demonstrated that treatment with BAY 41-2272 and BAY 58-2667 reduces the expression of tissue factor, which is linked to the initiation of coagulation but also both inflammation and atherosclerosis [25].…”

Section: Discussionmentioning

confidence: 99%

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants

et al. 2016

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Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the β1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the β1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

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Activation of soluble guanylyl cyclase prevents foam cell formation and atherosclerosis

Abstract: Activation of sGC by YC-1 leads to LXRα-dependent upregulation of ABCA1 in macrophages and may confer protection against atherosclerosis.

Cited by 31 publications

References 46 publications

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

Functional Characterization of the GUCY1A3 Coronary Artery Disease Risk Locus

The phosphatase activity of soluble epoxide hydrolase regulates ATP‐binding cassette transporter‐A1‐dependent cholesterol efflux

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants

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