Akap1genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice

Abstract

Critically ill patients are commonly treated with high levels of oxygen, hyperoxia, for prolonged periods of time. Unfortunately, extended exposure to hyperoxia can exacerbate respiratory failure and lead to a high mortality rate. Mitochondrial A-kinase anchoring protein (Akap) has been shown to regulate mitochondrial function. It has been reported that, under hypoxic conditions, Akap121 undergoes proteolytic degradation and promotes cardiac injury. However, the role of Akap1 in hyperoxia-induced acute lung injury (ALI) is largely unknown. To address this gap in our understanding of Akap1, we exposed wild-type ( wt) and Akap1 mice to 100% oxygen for 48 h, a time point associated with lung damage in the murine model of ALI. We found that under hyperoxia, Akap1 mice display increased levels of proinflammatory cytokines, immune cell infiltration, and protein leakage in lungs, as well as increased alveolar capillary permeability compared with wt controls. Further analysis revealed that Akap1 deletion enhances lung NF-κB p65 activity as assessed by immunoblotting and DNA-binding assay and mitochondrial autophagy-related markers, PINK1 and Parkin. Ultrastructural analysis using electron microscopy revealed that Akap1 deletion was associated with remarkably aberrant mitochondria and lamellar bodies in type II alveolar epithelial cells. Taken together, these results demonstrate that Akap1 genetic deletion increases the severity of hyperoxia-induced acute lung injury in mice.

A-Kinase Anchoring Protein 1: Emerging Roles in Regulating Mitochondrial Form and Function in Health and Disease

“…In addition to the above-mentioned increases in mitophagy upon AKAP1 deletion under hypoxia conditions, another study demonstrated that hyperoxia conditions also increase mitophagy in AKAP1 KO mice. Following 48 h of hyperoxia treatment, the study found significantly increased PINK1 and Parkin expression in the AKAP1 KO animals, along with elevation of a number of inflammatory cytokines in lung tissue [27]. While this study examined acute lung injury by prolonged exposure to high oxygen concentration and the other studies mentioned above looked at ischemic heart injuries, these studies collectively demonstrate the important role of AKAP1 in preserving mitochondrial functions to promote cell survival under the stressful conditions of both high and low oxygen levels.…”

“…The AKAP1 knockout mouse was generated by deletion of the first coding exon that includes the mitochondrial targeting sequence and the PKA binding site [22]. Even though the AKAP1 knockout mouse was generated over a decade ago [22], a recent flurry of publications has described the use of the AKAP1 gene deletion to tease out the function of AKAP1 in a variety of tissues [23][24][25][26][27][28]. As we begin to discuss the specific roles of AKAP1 in mitochondrial form and function, it is worth noting how the dynamic changes in mitochondrial morphology impact function.…”

“…Cardiomyocytes rely on proper mitochondrial function to support the high-energy demand required for contraction. Mitochondria are critical for cell survival in acute injuries to the heart and lungs, in part due to their ability to regulate cellular ROS generation and sequestration [27,45,46]. Therefore, AKAP1 is considered a cardioprotective scaffolding protein of PKA.…”

“…Looking into the future, generating a tissue-specific AKAP1 KO mouse could help us to further dissect the roles of AKAP1 in different diseases. In cardiovascular diseases, hyperoxia-induced lung injury and ischemia-induced neurodegeneration, AKAP1 has been shown to support cell survival [23][24][25]27,28,50]. However, all these studies described the loss of AKAP1 as being detrimental.…”

Protective Features of Autophagy in Pulmonary Infection and Inflammatory Diseases

“…Through regulating ATG7 promoter, OGG-1 links DNA damage with autophagy in stimulating NF-κB–mediated inflammatory response to protect hyperoxia–induced epithelial injury [71]. Hyperoxia also causes a morphological change in mitochondria accomplished with increased expression of mitophagy–associated markers (PINK1 and PARK2) in lung epithelial cells, implying that mitophagy might play a role in protecting epithelial cells from hyperoxia–induced injury [72]. It is worth noting that the hyperoxia–induced ROS accumulation, mitochondrial damage and autophagy were also observed in pulmonary endothelial cells [73,74].…”