Involvement of Circadian Clock Gene BMAL1 in Doxorubicin-Induced Inflammation in Vascular Smooth Muscle Cells
2021
The molecular clock component Brain
and Muscle Arnt-Like protein-1 (BMAL-1)
affects various biologic processes, including cell survival, in numerous cell
types. We previously demonstrated that BMAL1 positively regulates cell
proliferation in Vascular Smooth Muscle Cells (VSMCs). However, its role in
VSMC inflammation remains unelucidated. Because doxorubicin causes phlebitis
associated with vascular inflammation, the present study used cultured VSMCs to
investigate whether BMAL1 affected doxorubicin-induced vascular inflammation. Doxorubicin treatment led to Increased
Interleukin (IL)-6 mRNA expression with an
increase in BMAL1 expression in VSMCs. BMAL1
knockdown significantly increased IL-6 mRNA and further enhanced
doxorubicin-induced IL-6 mRNA expression in VSMCs. BMAL1 knockdown also significantly decreased cell viability and
affected the expression of other clock genes, including Per1 and Clock. Furthermore, the levels of
nuclear factor erythroid 2-related factor
2, which has anti-inflammatory effects, increased in VSMCs with BMAL1 knockdown. Finally, BMAL1
knockdown increased NADPH oxidase 4 mRNA, p38α mRNA, and p38β mRNA
levels, leading to increased total p38 Mitogen-Activated Protein Kinase (MAPK)
and phosphorylated p38 MAPK. IL-6 mRNA induction caused by BMAL1 knockdown was significantly
inhibited in VSMCs following pretreatment
with SB203580, a p38 MAPK inhibitor. Our findings demonstrated that decreased
BMAL1 expression caused VSMC inflammation via p38 MAPK activation.
Moreover, doxorubicin-induced inflammation in VSMCs was further enhanced when BMAL1 expression levels were low. Thus, BMAL1 may be a novel therapeutic target to
treat inflammatory disease, including doxorubicin-induced phlebitis.
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