Blocking NAD⁺/CD38/cADPR/Ca²⁺ pathway in sepsis prevents organ damage

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• 作者：Qian-Yi Peng ; PhD ; MD^a ; Mei-Lin Ai ; MD^a ; Li-Na Zhang ; PhD ; MD^a ; Yu Zou ; PhD ; MD^b ; Xin-Hua Ma ; MD^a ; Yu-Hang Ai ; PhD ; MD^a ; ^{ayhicu1978@126.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Nicotinamide adenine dinucleotide ; CD38 ; Cyclic ADP-ribose ; Calcium ions ; Sepsis
• 刊名：Journal of Surgical Research
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：201
• 期：2
• 页码：480-489
• 全文大小：2147 K

文摘

Although the nicotinamide adenine dinucleotide (NAD⁺)/CD38/cyclic ADP ribose (cADPR)/Ca²⁺ signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD⁺/CD38/cADPR/Ca²⁺ signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage.

Materials and methods

Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD⁺, cADPR, CD38, and intracellular Ca²⁺ levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin–eosin-stained and assayed for malondialdehyde and superoxide dismutase activities.

Results

NAD⁺, cADPR, CD38, and intracellular Ca²⁺ levels increased in the hearts, livers, and kidneys of septic rats as early as 6–24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca²⁺ mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats.

Conclusions

The NAD⁺/CD38/cADPR/Ca²⁺ signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.