Opposing Effects of PPARα Agonism and Antagonism on Refractive Development and Form Deprivation Myopia in Guinea Pigs

Invest. Ophthalmol. Vis. Sci.

et al. 2020

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In guinea pigs, choroidal thickness (ChT) and choroidal blood perfusion (ChBP) simultaneously decrease in experimental myopia, and both increase during recovery. However, the causal relationship between ChBP and myopia requires further investigation. In this study, we examined the changes of ChBP with three different antimyopia treatments. We also actively increased ChBP to examine the direct effect on myopia development in guinea pigs. METHODS. Experiment 1: Guinea pigs wore occluders on the right eye for two weeks to induce form-deprivation myopia (FDM). Simultaneously they received daily antimyopia treatments: peribulbar injections of atropine or apomorphine or exposure to intense light. Experiment 2: The vasodilator prazosin was injected daily into the form-deprivation eyes to increase ChBP during the two-week induction of FDM. Other FDM animals received appropriate control treatments. Changes in refraction, axial length, ChBP, ChT, and hypoxia-labeled pimonidazole adducts in the sclera were measured. RESULTS. The antimyopia treatments atropine, apomorphine, and intense light all significantly inhibited myopia development and the decrease in ChBP. The treatments also reduced scleral hypoxia, as indicated by the decrease in hypoxic signals. Furthermore, actively increasing ChBP with prazosin inhibited the progression of myopia, as well as the increase in axial length and scleral hypoxia. CONCLUSIONS. Our data strongly indicate that increased ChBP attenuates scleral hypoxia, and thereby inhibits the development of myopia. Thus ChBP may be a promising target for myopia retardation. As such, it can serve as an immediate predictor of myopia development as well as a long-term marker of it.

Section: Experimental Designmentioning

confidence: 99%

Increased Choroidal Blood Perfusion Can Inhibit Form Deprivation Myopia in Guinea Pigs

Zhou

Invest. Ophthalmol. Vis. Sci.

et al. 2020

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“…Previous studies have demonstrated that activation of the PPAR pathway leads to lipid degradation, 38 and lipid droplet depletion increases ER stress and inhibits cell activity by mediating apoptosis 39 . Combined RNA sequencing data indicated that treatment with MLT increases the expression of the PPARa pathway‐related genes CPT1C 40 and ME1 41 (Figure S3I). We hypothesized that MLT/CES1 mediates lipid depletion and apoptosis through the PPARa‐ER stress pathway.…”

Section: Resultsmentioning

confidence: 81%

Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1

Zhou

Clinical & Translational Med

Yang

et al. 2021

Background Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. Methods We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. Results We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta‐analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1‐knockout (Ces −/− ) mice verified the important role of endogenous Ces1 in PCa. Conclusions Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.

“…Although it is well established that the sclerae of humans and animal models are characterized by antifibrotic events during myopia, downregulation of scleral Pparα is consistent with an earlier study wherein PPARα antagonism induced myopia development in guinea pigs. 29 Formation of the PPARα:RXR complex is critical in mediating the expression of downstream genes. However, we showed here that butaprost injections reduced Rxra and Rxrb mRNA levels as well.…”

Section: Discussionmentioning

confidence: 99%

“…Axial length (AL) and vitreous chamber depth (VCD) were estimated using an A-scan ultrasonograph (AVISO Echograph Class I-Type Bat, frequency:11 MHz; Quantel Medical, Clermont-Ferrand, France) as previously described. 29 The refraction and axial length measurements were also obtained at the start of the experiment. After completing the two-week ocular measurements, the guinea pigs were terminally anesthetized with an overdose of chloral hydrate and euthanized via cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

“… 25 – 27 However, in the guinea pig sclera, PPARα agonism had a profibrotic effect that suppressed myopia progression, whereas PPARα antagonism inhibited fibrosis and promoted myopia. 28 , 29 We also earlier reported that a hypoxic environment in the sclera promotes myopia in mice and guinea pigs, while an inhibitor of hypoxia-inducible factor 1-alpha (HIF-1α), a known hypoxia marker, suppressed myopia development. Such myopia inhibitions were accompanied by COL1α1 downregulations in the latter model.…”

mentioning

confidence: 93%

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Crosstalk between EP2 and PPARα Modulates Hypoxic Signaling and Myopia Development in Guinea Pigs

Srinivasalu

Invest. Ophthalmol. Vis. Sci.

et al. 2020

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Purpose Cyclic adenosine monophosphate (cAMP) and peroxisome proliferator-activated receptor alpha (PPARα) levels mediate extracellular matrix (ECM) changes by altering the levels of hypoxia-inducible factor 1-alpha (HIF-1α) in various tissues. We aimed to determine, in the sclera of guinea pigs, whether a prostanoid receptor (EP2)-linked cAMP modulation affects PPARα and HIF-1α signaling during myopia. Methods Three-week-old guinea pigs (n = 20 in each group), were monocularly injected with either an EP2 agonist (butaprost 1 µmol/L/10 µmol/L), an antagonist (AH6809 10 µmol/L/30 µmol/L) or a vehicle solution for two weeks during normal ocular growth. Separate sets of animals received these injections and underwent form deprivation (FD) simultaneously. Refraction and axial length (AL) were measured at two weeks, followed by scleral tissue isolation for quantitative PCR (qPCR) analysis (n = 10) and cAMP detection (n = 10) using a radioimmunoassay. Results Butaprost induced myopia development during normal ocular growth, with proportional increases in AL and cAMP levels. FD did not augment the magnitude of myopia or cAMP elevations in these agonist-injected eyes. AH6809 suppressed cAMP increases and myopia progression during FD, but had no effect in a normal visual environment. Of the diverse set of 27 genes related to cAMP, PPARα and HIF-1α signaling and ECM remodeling, butaprost differentially regulated 15 of them during myopia development. AH6809 injections during FD negated such differential gene expressions. Conclusions EP2 agonism increased cAMP and HIF-1α signaling subsequent to declines in PPARα and RXR mRNA levels, which in turn decreased scleral fibrosis and promoted myopia. EP2 antagonism instead inhibited each of these responses. Our data suggest that EP2 suppression may sustain scleral ECM structure and inhibit myopia development.