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Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

ABSTRACT: Adiponectin (APN), an adipocyte-derived adipokine, has been shown to limit lung injury originating from endothelial cell (EC) damage. Previously we reported that obese mice with low circulatory APN levels exhibited pulmonary vascular endothelial dysfunction. This study was designed to investigate the cellular and molecular mechanisms underlying the pulmonary endothelium-dependent protective effects of APN. Our results demonstrated that in APN-/- mice, there was an inherent state of endothelium mitochondrial dysfunction that could contribute to endothelial activation and increased susceptibility to LPS-induced acute lung injury (ALI). We noted that APN-/- mice showed decreased expression of mitochondrial biogenesis regulatory protein peroxisome proliferator-activated receptor ? coactivator 1-? (PGC-1?) and its downstream proteins nuclear respiratory factor 1, transcription factor A, mitochondrial, and Sirtuin (Sirt)3 and Sirt1 expression in whole lungs and in freshly isolated lung ECs from these mice at baseline and subjected to LPS-induced ALI. We further showed that treating APN-/- mice with PGC-1? activator pyrroloquinoline quinone enhances mitochondrial biogenesis and function in lung endothelium and attenuation of ALI. These results suggest that the pulmonary endothelium-protective properties of APN are mediated, at least in part, by an enhancement of mitochondrial biogenesis through a mechanism involving PGC-1? activation.-Shah, D., Torres, C., Bhandari, V. Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

SUBMITTER: Shah D

PROVIDER: S-EPMC6894062 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

Shah Dilip D Torres Claudio C Bhandari Vineet V

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20191004 12

Adiponectin (APN), an adipocyte-derived adipokine, has been shown to limit lung injury originating from endothelial cell (EC) damage. Previously we reported that obese mice with low circulatory APN levels exhibited pulmonary vascular endothelial dysfunction. This study was designed to investigate the cellular and molecular mechanisms underlying the pulmonary endothelium-dependent protective effects of APN. Our results demonstrated that in APN<sup>-/-</sup> mice, there was an inherent state of en ...[more]

PMID: 31585050

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Project description:Loss-of-function mutations of the gene encoding Krev interaction trapped protein 1 (KRIT1) are associated with the pathogenesis of Cerebral Cavernous Malformation (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries and affecting 0.5% of the human population. However, growing evidence demonstrates that KRIT1 is implicated in the modulation of major redox-sensitive signaling pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, suggesting that its loss-of-function mutations may have pathological effects not limited to CCM disease. The aim of this study was to address whether KRIT1 loss-of-function predisposes to the development of pathological conditions associated with enhanced endothelial cell susceptibility to oxidative stress and inflammation, such as arterial endothelial dysfunction (ED) and atherosclerosis. Silencing of KRIT1 in human aortic endothelial cells (HAECs), coronary artery endothelial cells (HCAECs), and umbilical vein endothelial cells (HUVECs) resulted in increased expression of endothelial proinflammatory adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and in enhanced susceptibility to tumor necrosis factor alpha (TNF-α)-induced apoptosis. These effects were associated with a downregulation of Notch1 activation that could be rescued by antioxidant treatment, suggesting that they are consequent to altered intracellular redox homeostasis induced by KRIT1 loss-of-function. Furthermore, analysis of the aorta of heterozygous KRIT1+/- mice fed a high-fructose diet to induce systemic oxidative stress and inflammation demonstrated a 1.6-fold increased expression of VCAM-1 and an approximately 2-fold enhanced fat accumulation (7.5% vs 3.6%) in atherosclerosis-prone regions, including the aortic arch and aortic root, as compared to corresponding wild-type littermates. In conclusion, we found that KRIT1 deficiency promotes ED, suggesting that, besides CCM, KRIT1 may be implicated in genetic susceptibility to the development of atherosclerotic lesions.

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Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

Publications

Adiponectin deficiency induces mitochondrial dysfunction and promotes endothelial activation and pulmonary vascular injury.

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