Aortic wall
inflammation, abnormal oxidative stress and progressive degradation of
extracellular matrix proteins are the main characteristics of
abdominal aortic aneurysms (AAAs). The
nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)
inflammasome dysregulation plays a crucial role in aortic damage and
disease progression. The first aim of this study was to examine the effect of
baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one) on AAA formation in
apolipoprotein E-deficient (
ApoE-/-) mice. The second aim was to define whether
baicalein attenuates aberrant vascular smooth muscle cell (VSMC) proliferation and
inflammation in VSMC culture. For male
ApoE-/- mice, a clinically relevant AAA model was randomly divided into four groups: saline infusion,
baicalein intraperitoneal injection,
Angiotensin II (Ang II) infusion and Ang II +
baicalein. Twenty-seven days of treatment with
baicalein markedly decreased Ang II-infused AAA incidence and aortic diameter, reduced
collagen-fiber formation, preserved elastic structure and density and prevented smooth muscle cell
contractile protein degradation.
Baicalein inhibited rat VSMC proliferation and migration following the stimulation of VSMC cultures with Ang II while blocking the Ang II-inducible cell cycle progression from G0/G1 to the S phase in the synchronized cells. Cal-520 AM staining showed that
baicalein decreased cellular
calcium in Ang II-induced VSMCs; furthermore, a Western blot assay indicated that
baicalein inhibited the expression of
PCNA and significantly lowered levels of phospho-Akt and phospho-ERK, along with an increase in
baicalein concentration in Ang II-induced VSMCs. Immunofluorescence staining showed that
baicalein pretreatment reduced NF-κB nuclear translocation in Ang II-induced VSMCs and furthered the
protein expressions of NLRP3 while ASC and caspase-1 were suppressed in a dose-dependent manner.
Baicalein pretreatment upregulated Nrf2/HO-1 signaling in Ang II-induced VSMCs. Thus,
2',7'-dichlorodihydrofluorescein diacetate (
DCFH-DA) staining showed that its
reactive oxygen species (ROS) production decreased, along with the
baicalein pretreatment. Our overall results indicate that
baicalein could have therapeutic potential in preventing
aneurysm development.