Thyroid Hormone Receptor Alpha Deletion in ApoE&lt;sup&gt;–/–&lt;/sup&gt; Mice Alters the Arterial Renin-Angiotensin System and Vascular Smooth Muscular Cell Cholesterol Metabolism

Neggazi, Samia; Canaple, Laurence; Hamlat, Nadjiba; Gauthier, Karine; Samarut, Jacques; Bricca, Giampiero; Aouichat-Bouguerra, S.; Beylot, M.

doi:10.1159/000491430

Cited by 5 publications

(2 citation statements)

References 34 publications

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“…S3), which aligns with a reported role of MEF2C in driving VSMC differentiation (Pagiatakis et al, 2012). Thyroid hormone receptor alpha (THRA) that has been suggested to impact VSMC cholesterol metabolism (Neggazi et al, 2018), was also a central node in all networks (Fig. 2D).…”

Section: Rewiring Of Shared Factors Between Injury-induced Vsmc Statessupporting

confidence: 83%

Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease

Lambert,

Oc,

Worssam

et al. 2023

Preprint

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Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation are hallmarks of vascular diseases causing heart attack and stroke. To elucidate molecular determinants governing VSMC proliferation, we reconstructed gene regulatory networks from single cell transcriptomics and epigenetic profiling. We find progressive activation of enhancers at disease-relevant loci in VSMCs that don’t respond to injury and proliferation-predisposed cells. Our analysis suggests that while many transcription factors are shared, their target loci differ between VSMC states. Comparison of rewiring between VSMC subsets andin silicoperturbation analysis prioritised novel regulators, including RUNX1 and the network target TIMP1. We experimentally validated that the pioneer factor RUNX1 increased VSMC responsiveness and show that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signalling. Both RUNX1 and the TIMP1-CD74 axis were expressed in hVSMCs, at low frequency in normal arteries and increased in disease, suggesting clinical significance and potential as novel vascular disease targets.

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Section: Rewiring Of Shared Factors Between Injury-induced Vsmc Statessupporting

confidence: 83%

Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease

Lambert,

Oc,

Worssam

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The factors predicted to block trajectory progression (positive KO score > 1) were enriched for TGF-beta signaling (KEGG:04350), IL-17 signaling (KEGG:04657) and parathyroid hormone synthesis, secretion and action (KEGG:04928). Interestingly, thyroid hormone receptor alpha (THRA), which has been suggested to impact VSMC cholesterol metabolism 29 , was among trajectory-blocking factors (Fig. 4d ).…”

Section: Prioritization Of Candidate Regulators Of Vsmc Activationmentioning

confidence: 99%

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease

Lambert,

Oc,

Worssam

et al. 2024

Nat Cardiovasc Res

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Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.

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Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus

Neggazi,

Hamlat,

Berdja

et al. 2023

Sci Rep

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It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.

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Thyroid Hormone Receptor Alpha Deletion in ApoE<sup>–/–</sup> Mice Alters the Arterial Renin-Angiotensin System and Vascular Smooth Muscular Cell Cholesterol Metabolism

Cited by 5 publications

References 34 publications

Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease

Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease

Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus

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