Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
Gene/Protein
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Query: UMLS:C0162871 (
abdominal aortic aneurysm
)
8,664
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Abdominal aortic aneurysm
(
AAA
) is a vascular degenerative disease. Macrophage polarization and the balance between classically activated macrophages (M1) and alternatively activated macrophages (M2) are crucial for
AAA
pathogenesis. The present study aims to investigate the roles of macrophage
SIRT1
in
AAA
formation and macrophage polarization. We found that in mouse peritoneal macrophages,
SIRT1
expression was decreased after M1 stimulation, but was enhanced after M2 stimulation. Results from
SIRT1
flox/flox
mice and macrophage specific
SIRT1
knockout mice with treatment of angiotensin II (Ang II) for 4 weeks showed that macrophage specific deficiency of
SIRT1
increased the incidence of
AAA
and exacerbated the severity, including more severe aneurysm types, enlarged diameter of the aneurysm and increased degradation of elastin. In mouse aortas,
SIRT1
deficiency increased the pro-inflammatory M1 molecule inducible nitric oxide synthase (iNOS), and decreased M2 molecules such as arginase 1 (Arg1) and mannose receptor (MR). Furthermore, in peritoneal macrophages,
SIRT1
deficiency increased the expression of M1 inflammatory molecules, but decreased the expression of M2 molecules. Overexpression of
SIRT1
had the opposite effects. Thus, macrophage specific knockout of
SIRT1
influences macrophage polarization and accelerates Ang II-induced
AAA
formation.
...
PMID:Mouse macrophage specific knockout of SIRT1 influences macrophage polarization and promotes angiotensin II-induced abdominal aortic aneurysm formation. 2939 44
Identifying effective drugs to delay the progression of aortic aneurysms is a formidable challenge in vascular medicine. Methyltransferase-like 3 (METTL3) plays a key role in catalyzing the formation of N6-methyladenosine (m
6
A), but despite the functional importance of METTL3 and m
6
A in various fundamental biological processes, their roles in
abdominal aortic aneurysm
(
AAA
) are unknown. Here, we found that METTL3 knockdown in apolipoprotein E-deficient (ApoE
-/-
) mice treated with angiotensin II suppressed the formation of AAAs, while METTL3 overexpression exerted the opposite effects. Similar results were obtained in a calcium chloride (CaCl
2
)-induced mouse
AAA
model. Mechanistically, METTL3-dependent m
6
A methylation promoted primary microRNA-34a (miR-34a, pri-miR34a) maturation through DGCR8. Moreover, miR-34a overexpression significantly decreased
SIRT1
expression and aggravated
AAA
formation, while miR-34a deficiency produced the opposite effects. In a rescue experiment, miR-34a knockdown or forced expression of
SIRT1
partially attenuated the protective effects of METTL3 deficiency against
AAA
formation. Our studies reveal an important role for METTL3/m
6
A-mediated miR-34a maturation in
AAA
formation and provide a novel therapeutic target and diagnostic biomarker for
AAA
treatment.
...
PMID:METTL3 Induces AAA Development and Progression by Modulating N6-Methyladenosine-Dependent Primary miR34a Processing. 3265 Feb 37
Vascular smooth muscle cells (VSMCs), located in the media of artery, play key roles in maintaining the normal vascular physiological functions. Abnormality in VSMCs is implicated in vascular diseases (VDs), including atherosclerosis,
abdominal aortic aneurysm
(
AAA
), aortic dissection, and hypertension by regulating the process of inflammation, phenotypic switching, and extracellular matrix degradation. Sirtuins (SIRTs), a family of proteins containing seven members (from
SIRT1
to SIRT7) in mammals, function as NAD
+
-dependent histone deacetylases and ADP-ribosyltransferases. In recent decades, great attention has been paid to the cardiovascular protective effects of SIRTs, especially
SIRT1
, suggesting a new therapeutic target for the treatment of VDs. In this review, we introduce the basic functions of
SIRT1
against VSMC senescence, and summarize the contribution of
SIRT1
derived from VSMCs in VDs. Finally, the potential new strategies based on
SIRT1
activation have also been discussed with an emphasis on
SIRT1
activators and calorie restriction to improve the prognosis of VDs.
...
PMID:Histone Deacetylase SIRT1, Smooth Muscle Cell Function, and Vascular Diseases. 3311 55
