Adiponectin ameliorates lung ischemia\u2013reperfusion injury through SIRT1-PINK1 signaling-mediated mitophagy in type 2 diabetic rats

Tao Jiang,Tao Jiang,Wanchao Yang,Xiangqi Lv,Ziyong Yue,Tianhua Liu,Tianhua Liu,Wengang Ding,Wenzhi Li,Xijin Deng,Wanchao Yang,Ziyong Yue,Xiangqi Lv,Wengang Ding

doi:10.1186/s12931-021-01855-0

Abstract

BackgroundDiabetes mellitus (DM) is a key contributing factor to poor survival in lung transplantation recipients. Mitochondrial dysfunction is recognized as a critical mediator in the pathogenesis of diabetic lung ischemia–reperfusion (IR) injury. The protective effects of adiponectin have been demonstrated in our previous study, but the underlying mechanism remains unclear. Here we demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury.MethodsHigh-fat diet-fed streptozotocin-induced type 2 diabetic rats were exposed to adiponectin with or without administration of the SIRT1 inhibitor EX527 following lung transplantation. To determine the mechanisms underlying the action of adiponectin, rat pulmonary microvascular endothelial cells were transfected with SIRT1 small-interfering RNA or PINK1 small-interfering RNA and then subjected to in vitro diabetic lung IR injury.ResultsMitophagy was impaired in diabetic lungs subjected to IR injury, which was accompanied by increased oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction. Adiponectin induced mitophagy and attenuated subsequent diabetic lung IR injury by improving lung functional recovery, suppressing oxidative damage, diminishing inflammation, decreasing cell apoptosis, and preserving mitochondrial function. However, either administration of 3-methyladenine (3-MA), an autophagy antagonist or knockdown of PINK1 reduced the protective action of adiponectin. Furthermore, we demonstrated that APN affected PINK1 stabilization via the SIRT1 signaling pathway, and knockdown of SIRT1 suppressed PINK1 expression and compromised the protective effect of adiponectin.ConclusionThese data demonstrated that adiponectin attenuated reperfusion-induced oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of SIRT1- PINK1 signaling-mediated mitophagy in diabetic lung IR injury.

Highlights

Lung transplantation remains definitive therapy for endstage respiratory failure with no other treatment options [1]
Measurement of mitochondrial morphology The mitochondrial disruption was evaluated by the Flameng score [33] as follows: 0, structures are normal and Diabetes reduces lung IR‐induced mitophagy, and APN restores diabetic lung IR‐reduced mitophagy via Silent information regulator 1 (SIRT1) We have reported that impaired lung SIRT1 signaling associated with type 2 diabetic conditions was further attenuated by IR injury in a warm lung IR model [17]
APN upregulated PTEN induced putative kinase 1 (PINK1)‐dependent mitophagy via the SIRT1 signaling pathway in pulmonary microvascular endothelial cells (PMVECs) subjected to diabetic IR injury we explored some insights into the regulation of mitophagy in our experimental models, and PMVECs infected with PINK1 Short interfering RNA (siRNA) or SIRT1 siRNA

Summary

Introduction

Lung transplantation remains definitive therapy for endstage respiratory failure with no other treatment options [1]. Approximately 15% of recipients undergoing lung transplantation experience graft complications due to lung ischemia reperfusion (IR) injury [2]. Lung IR injury is still the major risk factor for postoperative complications, such as acute graft rejection and obliterative bronchiolitis [6]. Extensive efforts have been dedicated to exploring the rescue strategies for lung IR injury in the diabetic state. Our previous study showed that DM aggravated lung IR injury, and mitochondrial dysfunction was a pivotal factor in this process [9]. Preservation of mitochondrial function is significant in the management of patients with pretransplant DM who undergo lung transplantation. Diabetes mellitus (DM) is a key contributing factor to poor survival in lung transplantation recipients. We demonstrated an important role of mitophagy in the protective effect of adiponectin during diabetic lung IR injury

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