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Aims This study aims to investigate the pathophysiological role and mechanism of pigment epithelium-derived factor (PEDF) deletion in ovarian damage. Methods Female PEDF-knockout mice and their wild-type littermates were used in this study. Relevant tests were performed at 8–10 weeks or 32 weeks of age. Key findings Compared to the wild-type mice, the PEDF-knockout mice showed diminished ovarian reserve (DOR), worse ovum quality after injection to induce controlled ovarian stimulation, increased serum follicle stimulating hormone (FSH) level and an follicle stimulating hormone/luteinizing hormone (FSH/LH) ratio. Moreover, severe ovarian oxidative damage was found in ovaries of PEDF-knockout mice that mainly manifested as an accumulation of reactive oxygen species (ROS), NF‑E2-related factor 2 (Nrf2) pathway activation, significantly upregulated expression of ROS-generating genes. Correspondingly, the PEDF-knockout mice exhibited lipid metabolism disorder and insulin resistance, which mainly manifested as obesity, abdominal fat accumulation, adipocyte enlargement, severe ectopic fat deposition, dyslipidemia, changes in adipokine levels, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, impaired insulin tolerance and significantly declined protein kinase B (Akt) phosphorylation levels. Significance Loss of PEDF leads to ovarian oxidative damage accompanied by DOR in mice, this is related to PEDF deficiency induced severe insulin resistance and lipid metabolism disorder. Therefore, PEDF may be a potential target for the treatment of diseases related to ovarian oxidative damage.

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. The myocardial energy metabolism was recently reported to be related to the loss of proliferation capacity in cardiomyocyte (CM). However, the intrinsic relationship between beating rate and proliferation in CM and whether energy metabolism can regulate this relationship is not known. In this study, we found that limited HRR induced CM proliferation under physiological conditions and promoted cardiac regenerative repair after myocardial injury. Mechanistically, limited HRR induced G1/S transition and increased the expression of glycolytic enzyme in CMs. Furthermore, limited HRR induced a unique metabolic pattern switch (activating glucose metabolism and increased the relative proportion of ATP production by the glycolytic pathway) for the biosynthesis of substrates needed for proliferative CM. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restore.

Background: Pigment epithelial-derived factor (PEDF) is protectively involved in atherosclerosis induced by hyperlipidemia, but expression characteristics of PEDF and the role of PEDF in the later stage of progressive atherosclerosis remain unclear. Methods: Circulating PEDF were analyzed in patients with atherosclerotic cardiovascular disease (ASCVD) and in murine models of wildtype (WT) mice and ApoE-/- mice under long-term high-fat diet (HFD). PEDF-/-/ ApoE-/- mice and matching PEDF+/+/ ApoE-/- mice fed with HFD for 24, 36 and 48 weeks, combined with injections of adeno-associated virus encoding PEDF (AAV-PEDF) in ApoE-/-/PEDF-/- mice were used to investigate the effects of PEDF knockdown on vascular function and structure. Experiments in vitro and in vivo were applied to identify PEDF regulate vascular endothelial growth factor (VEGFB) signaling pathway mediated endothelial fatty acid (FA) uptake. Findings: Circulating PEDF was increased in ASCVD patients compared to normal individuals, while decreasing trends were confirmed in murine models of WT mice and ApoE-/- mice on long-term HFD. ApoE-/-/PEDF-/- mice placed on HFD were fatter and had accelerated atherosclerotic formation, as evidenced by higher serum lipid levels, increased atherosclerotic plaques, pronounced vascular dysfunction and increased lipid accumulation in peripheral tissues, whereas injections of AAV-PEDF in ApoE-/-/PEDF-/- mice significantly improved. Mechanistically, PEDF deletion activated VEGFB paracrine signaling by upregulating expressions of VEGFB in peripheral tissues and its downstream targets on endothelial cells, including its receptors, namely VEGFR1 and neuropilin-1, and fatty acid transport protein 3 and 4 to enhance FA uptake. Interpretation: Decreasing expression of PEDF may decompensate to aggravate atherosclerosis. Funding: National Nature Science Foundation of China, Science and Technology Project of Guangzhou. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study was approved by the ethical committees of Sun Yat-sen Memorial Hospital and Sun Yat-sen University.