Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis

I-Ta Lee; Chien-Chung Yang; Yan-Jyun Lin; Wen-Bin Wu; Wei-Ning Lin; Chiang-Wen Lee; Hui-Ching Tseng; Fuu-Jen Tsai; Li-Der Hsiao; Chuen-Mao Yang

doi:10.1002/tox.24429

Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis

Environ Toxicol. 2024 Oct 21. doi: 10.1002/tox.24429. Online ahead of print.

Authors

I-Ta Lee¹, Chien-Chung Yang^{2

3}, Yan-Jyun Lin⁴, Wen-Bin Wu^{5

6}, Wei-Ning Lin⁶, Chiang-Wen Lee^{7

8

9}, Hui-Ching Tseng¹⁰, Fuu-Jen Tsai^{11

12

13}, Li-Der Hsiao⁶, Chuen-Mao Yang⁶

Affiliations

¹ School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan.
² Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Taoyuan, Taoyuan, Taiwan.
³ School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Institute of Translational Medicine and new Drug Development, College of Medicine, China Medical University, Taichung, Taiwan.
⁵ School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
⁶ Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan.
⁷ Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi, Taiwan.
⁸ Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan.
⁹ Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
¹⁰ Research Center for Chinese Herbal Medicine, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
¹¹ School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan.
¹² Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
¹³ Division of Medical Genetics, China Medical University Children's Hospital, Taichung, Taiwan.

PMID: 39431643
DOI: 10.1002/tox.24429

Abstract

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47^phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.

Keywords: antioxidant; anti‐inflammation; carbon monoxide; heme oxygenase‐1; mevastatin; reactive oxygen species.

Abstract

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