Treatment with PFKFB3 inhibitor potentially improves diastolic function and arterial stiffness in PHD2ECKO mice

Abstract

AIMS: Arterial stiffness is a central factor of cardiovascular disease states and etiologies, such as hypertension and heart failure. Currently there is no available therapy to effectively target arterial stiffness. An oxygen sensing protein, prolyl hydroxylase domain-2 (PHD), is an emerging novel target for vascular remodeling. Previous studies have shown that specific deletion of PHD2 in the endothelium (PHD2ECKO) results in upregulation of hypoxia inducible factor (HIF), a crucial regulator of oxygen homeostasis. HIF affects several pathways, such as angiogenesis and energy metabolism. A glycolytic enzyme, 6-phosphofructo-2-kinase/fructose 2,6-biphosphatase 3 (PFKFB3), produces fructose 2,6-biphosphate. This metabolite allosterically activates phosphofructokinase 1 (PFK1), a rate-limiting enzyme of glycolysis. This study investigates the effects of PFKFB3 inhibition on PHD2ECKO mice using (2E)-3-(3-Pyridinyl)-1-(4-pyridinyl)-2-propen-1-one [3PO]. We hypothesize that treatment with 3PO will attenuate arterial stiffness in PHD2ECKO mice, thus leading to significant improvement in cardiac function. METHODS AND RESULTS: PHD2ECKO and PHD2f/f mice were injected with 3PO (25mg/kg/day) for 14 days i.p. Echocardiographic measurements were performed prior to treatment and at 2 weeks of treatment with 3PO. Blood pressure measurements were performed for three consecutive days of week one and week two.Echocardiography showed improvement of diastolic function in PHD2ECKO mice post-treatment with 3PO. This was exhibited by significant reductions in diastolic diameter and diastolic volume. Pulse wave velocity (PWV) is decreased, while coronary reserve flow (CFR) is increased post-treatment of the PFKFB3 inhibitor. Though these results are not significant, this notably shows some improvement in arterial stiffness. Blood pressure measurements showed improvements in systolic and diastolic blood pressure for PHD2ECKO mice. Systolic and diastolic blood pressure significantly decreased post-treatment of 3PO. CONCLUSIONS: Inhibition of PFKFB3 in endothelium PHD2 deficient mice improves diastolic cardiac function. Though insignificant, there was an improvement of arterial stiffness. Results showed a slight increase in CRF and decrease in PWV. This suggests that the glycolytic pathway can be a therapeutic target in cardiac function and arterial stiffness. This work was supported by National Institute of General Medical Sciences and National Heart, Lung, and Blood Institute (R01HL151536, JX Chen), the National Heart, Lung, and Blood Institute (R56HL164321, H. Zeng). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.