Leigh, T. | Search bioRxiv

bioRxiv2019

Activation or inhibition of PPARα-mediated fatty acid β-oxidation does not active cardiomyocyte proliferation in normal or infarcted adult mice

ObjectivesPPAR genes are known as the important regulators of fatty acid oxidation and energy homeostasis. PPAR is highly expressed in the embryonic and adult heart. Previous studies from infant mouse hearts have suggested that activation of PPAR using GW7647 treatment or cardiac-restricted activation of PPAR using MHC-PPAR transgenic mice enhanced fatty acid {beta}-oxidation and promoted cardiomyocyte proliferation rate in the postnatal day 4 mouse heart. Here, we further investigate the impact of PPAR-mediated fatty acid {beta}-oxidation on cardiomyocyte proliferation in the adult mouse heart.\n\nMethods and ResultsAdult wild-type (C57BL/6J) mice were subjected to five injections of GW7647, a highly specific PPAR agonist, or vehicle (saline). Cardiomyocyte proliferation was analyzed by quantification of DNA synthesis via ethynyldeoxyuridine (EdU) incorporation and quantification of cells undergoing mitosis using phosphorylated histone H3 (PH3). GW7647 treatment resulted in activation of PPAR target genes associated with fatty acid metabolism and {beta}-oxidation, validating its biological activity. However, GW7647 treatment did not active cardiomyocyte proliferation in the normal heart. In parallel, mice were subjected to myocardial infarction (MI) using permanent coronary artery occlusion. Both GW7647-treatd wild-type mice and MHC-PPAR transgenic mice showed no significant differences in cardiomyocyte DNA synthesis and mitosis compared with vehicle-treated wild-type mice after MI. Furthermore, inhibition of PPAR-mediated fatty acid {beta}-oxidation using etomoxir (ETO) treatment had no impact on cardiomyocyte proliferation in both normal and infarcted hearts of wild-type mice compared with vehicle treatment.\n\nSummaryThese findings suggest that activation or inhibition of PPAR-mediated fatty acid {beta}-oxidation did not active cardiomyocyte proliferation in normal or infarcted hearts of adult mice. Any effects on cardiac function observed following PPAR activation treatment is independent of enhanced cardiomyocyte renewal in the adult heart.

cell biology↗

bioRxiv2019

Endothelial sphingosine 1-phosphate receptors promote vascular normalization to influence tumor growth and metastasis

Sphingosine 1-phosphate receptor-1 (S1PR1) is essential for embryonic vascular development and maturation. In the adult, it is a key regulator of vascular barrier function and inflammatory processes. Its roles in tumor angiogenesis, tumor growth and metastasis are not well understood. In this report, we show that S1PR1 is expressed and active in tumor vessels. Tumor vessels that lack S1PR1 (S1pr1 ECKO) show excessive vascular sprouting and branching, decreased barrier function, and poor perfusion accompanied by loose attachment of pericytes. Compound knockout of S1pr1, 2 and 3 genes further exacerbated these phenotypes, suggesting compensatory function of endothelial S1PR2 and 3 in the absence of S1PR1. On the other hand, tumor vessels with high expression of S1PR1 (S1pr1 ECTG) show less branching, tortuosity and enhanced pericyte coverage. Larger tumors and enhanced lung metastasis were seen in S1pr1 ECKO whereas S1pr1 ECTG showed smaller tumors and reduced metastasis. Furthermore, anti-tumor activity of doxorubicin was more effective in S1pr1 ECTG than the wild-type counterparts. These data suggest that tumor endothelial S1PR1 induces vascular normalization and influences tumor growth, evolution and spread. Strategies to enhance S1PR1 signaling in tumor vessels may be an important adjunct to standard cancer therapy.\n\nSignificanceEndothelial sphingosine 1-phosphate receptors modulate tumor angiogenesis by inducing vascular normalization, which allows better blood circulation and enhanced anti-tumor therapeutic efficacy.

cancer biology↗