FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease

Januszewski, Andrzej S.; Watson, Chris; O’Neill, Vikki; McDonald, Kenneth; Ledwidge, Mark; Robson, Tracy; Jenkins, Alicia J.; Keech, Anthony; McClements, Lana

doi:10.1038/s41598-020-78676-6

Cited by 24 publications

(26 citation statements)

References 35 publications

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“…Therefore, ELISA was performed on rat heart protein lysates and immunofluorescent staining of sectioned tissue, which indeed confirmed an overall increase in FKBPL protein levels in RUPP hearts. This is aligned with the positive correlation observed previously between FKBPL plasma levels and diastolic dysfunction or BNP plasma levels in human samples [ 20 ]. Recent studies show that FKBPL regulates inflammatory STAT3 signalling, via CD44 and NFkB, which are both implicated in preeclampsia [ 26 , 53 , 64 , 65 ].…”

Section: Discussionsupporting

confidence: 91%

“…A novel anti-angiogenic protein, FK506-binding protein like (FKBPL), has recently been identified as having predictive and diagnostic roles in preeclampsia [ 19 ] as well as being a determinant of CVD [ 20 ]. FKBPL is a divergent member of the immunophilin group that shares similar structure and functions to the FKBP members but lacks an essential residue in its peptidyl prolyl isomerases (PPIase) domain preventing its ability to exert this catalytic activity [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

et al. 2021

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Background Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. Methods The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein expression (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). Conclusions The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

et al. 2021

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“…In relation to angiogenesis, although no changes were observed at the mRNA level, FKBPL at the protein level was signi cantly increased following exposure to nicotine e-Cig aerosol. Similarly, CD31 22,50 , was also increased following exposure to e-Cig aerosol with nicotine, perhaps as part of the compensatory mechanism. The determinant factor for these results appears to involve the presence of nicotine, which has been shown to have pro-angiogenic properties 14 .…”

Section: Discussionmentioning

confidence: 92%

E-cigarette Aerosol Condensate leads to Impaired Coronary Endothelial Cell Health and Restricted Angiogenesis

Chhor

Tulpar

Nguyen

et al. 2022

Preprint

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Cardiovascular disease (CVD) is a leading cause of mortality worldwide, with cigarette smoking being a major preventable risk factor. Smoking cessation can be difficult due to the addictive nature of nicotine and the withdrawal symptoms following cessation. Electronic cigarettes (e-Cigs) have emerged as an alternative smoking cessation device, which has been increasingly used by non-smokers; however, the cardiovascular effects surrounding the use of e-Cigs remains unclear. This study aimed to investigate the effects of e-Cig aerosol condensate (EAC) (0mg and 18mg nicotine) in-vitro on human coronary artery endothelial cells (HCAEC) and in-vivo on the cardiovascular system using a mouse model of ‘e-vaping’. The results show a decrease in cell viability of HCAEC when exposed to EAC either directly or after exposure to conditioned lung cell media (p < 0.005). Reactive oxygen species and ICAM-1 expression were increased in HCAEC when exposed to EAC directly (p < 0.0005). ICAM-1 mRNA expression was increased (18mg vs control, p < 0.05), and immunostaining revealed upregulated anti-angiogenic markers, FKBPL, and endothelial cell marker, CD31, in murine hearts following exposure to electronic cigarette aerosol treatment. This study showed that even though e-Cigs are widely used for tobacco smoking cessation, these can negatively impact on endothelial cell health with a potential to lead to the development of cardiovascular disease. This process is visualised in Supplementary File 1.

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“…However, additional risk factors for vascular dementia include hypertension, low education in early life, alcohol consumption, and tobacco use that can limit treatment efficacy [3,22,31,[59][60][61]. In regard to metabolic disorders, early diagnosis and treatment of DM may offer some degree of protection to inhibit disease progression, but tight serum glucose control cannot completely prevent the complications from DM [5,8,16,[62][63][64][65][66][67][68][69][70][71]. In light of the present challenges to overcome cognitive loss, innovative therapeutic strategies are necessary to develop new treatments for dementia.…”

Section: Novel Therapeutic Considerations For Cognitive Lossmentioning

confidence: 99%

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

Maiese

2021

Biomolecules

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Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.

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FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease

Cited by 24 publications

References 35 publications

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

E-cigarette Aerosol Condensate leads to Impaired Coronary Endothelial Cell Health and Restricted Angiogenesis

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

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