Nicotine aggravates pancreatic fibrosis in mice with chronic pancreatitis via mitochondrial calcium uniporter

Xue Wei; Yue Yuan; Miaomiao Li; Zhiren Li; Xinye Wang; Haoxuan Cheng; Xinjuan Liu; Jianyu Hao; Tong Jin

doi:10.18332/tid/186587

Nicotine aggravates pancreatic fibrosis in mice with chronic pancreatitis via mitochondrial calcium uniporter

Tob Induc Dis. 2024 Apr 29:22. doi: 10.18332/tid/186587. eCollection 2024.

Authors

Xue Wei¹, Yue Yuan¹, Miaomiao Li¹, Zhiren Li¹, Xinye Wang¹, Haoxuan Cheng¹, Xinjuan Liu¹, Jianyu Hao¹, Tong Jin¹

Affiliation

¹ Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.

Abstract

Introduction: This study aimed to investigate the effects of nicotine on the activation of pancreatic stellate cells (PSCs) and pancreatic fibrosis in chronic pancreatitis (CP), along with its underlying molecular mechanisms.

Methods: This was an in vivo and in vitro study. In vitro, PSCs were cultured to study the effects of nicotine on their activation and oxidative stress. Transcriptome sequencing was performed to identify potential signaling pathways involved in nicotine action. And the impact of nicotine on mitochondrial Ca²⁺ levels and Ca²⁺ transport-related proteins in PSCs was analyzed. The changes in nicotine effects were observed after the knockdown of the mitochondrial calcium uniporter (MCU) in PSCs. In vivo experiments were conducted using a mouse model of CP to assess the effects of nicotine on pancreatic fibrosis and oxidative stress in mice. The alterations in nicotine effects were observed after treatment with the MCU inhibitor Ru360.

Results: In vitro experiments demonstrated that nicotine promoted PSCs activation, characterized by increased cell proliferation, elevated α-SMA and collagen expression. Nicotine also increased the production of reactive oxygen species (ROS) and cellular malondialdehyde (MDA), exacerbating oxidative stress damage. Transcriptome sequencing revealed that nicotine may exert its effects through the calcium signaling pathway, and it was verified that nicotine elevated mitochondrial Ca2+ levels and upregulated MCU expression. Knockdown of MCU reversed the effects of nicotine on mitochondrial calcium homeostasis, improved mitochondrial oxidative stress damage and structural dysfunction, thereby alleviating the activation of PSCs. In vivo validation experiments showed that nicotine significantly aggravated pancreatic fibrosis in CP mice, promoted PSCs activation, exacerbated pancreatic tissue oxidative stress, and increased MCU expression. However, treatment with Ru360 significantly mitigated these effects.

Conclusions: This study confirms that nicotine upregulates the expression of MCU, leading to mitochondrial calcium overload and exacerbating oxidative stress in PSCs, and ultimately promoting PSCs activation and exacerbating pancreatic fibrosis in CP.

Keywords: chronic pancreatitis; mitochondrial calcium homeostasis; nicotine; oxidative stress; pancreatic stellate cells.

Grants and funding

FUNDING This work was supported by the National Natural Science Foundation of China (Grant number 82070656) and Golden Seed Research Fund (Grant number CYJZ202222). The authors bear full responsibility for the content, and the views expressed in this article do not necessarily reflect the official opinions of the National Natural Science Foundation of China and Golden Seed Research Fund.