Abstract
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.
Highlights
Doxorubicin is a highly potent, effective broad-spectrum anticancer chemotherapeutic drug used to treat various cancers, including solid and hematologic tumors
Brain and Muscle Arnt-Like protein-1 (BMAL1) mRNA (Figure 1(c)) and BMAL1 protein (Figure 1(d)) expression were significantly increased following the treatment, indicating that doxorubicin modulated the expression of clock gene BMAL1 at a transcriptional level in Vascular Smooth Muscle Cells (VSMCs)
Increased IL-6 mRNA expression due to BMAL1 knockdown was significantly inhibited following pretreatment with SB203580, a p38 Mitogen-Activated Protein Kinase (MAPK) inhibitor (Figure 4(f)). These results suggest that p38 MAPK activation played a critical role in increased IL-6 mRNA expression VSMCs with BMAL1 knockdown
Summary
Doxorubicin is a highly potent, effective broad-spectrum anticancer chemotherapeutic drug used to treat various cancers, including solid and hematologic tumors. Because it elicits dose-dependent toxic side effects associated with cardiotoxicity, leading to dilated cardiomyopathy and heart failure [1] [2], its clinical use is limited. Clock genes form transcription-translational feedback loops that maintain circadian rhythms [7] [8] [9]. BMAL1 forms a heterodimer with a clock circadian regulator (CLOCK) and its heterodimers, which bind to the E-box element, increasing the expression of genes such as PER and CRY, which code for the Period Circadian Regulator (PER) and Cryptochrome Circadian Regulator (CRY), respectively. RORs activate the transcriptional expression of BMAL1, whereas REV-ERBs repress it by binding to the ROR element [11] [12]
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