OPLAH ablation leads to accumulation of 5-oxoproline, oxidative stress, fibrosis, and elevated fillings pressures: a murine model for heart failure with a preserved ejection fraction

Cardiovascular Research
Atze van der PolPeter van der Meer

Abstract

The prevalence of heart failure with a preserved ejection fraction (HFpEF) is increasing, but therapeutic options are limited. Oxidative stress is suggested to play an important role in the pathophysiology of HFpEF. However, whether oxidative stress is a bystander due to comorbidities or causative in itself remains unknown. Recent results have shown that depletion of 5-oxoprolinase (OPLAH) leads to 5-oxoproline accumulation, which is an important mediator of oxidative stress in the heart. We hypothesize that oxidative stress induced by elevated levels of 5-oxoproline leads to the onset of a murine HFpEF-like phenotype. Oplah full body knock-out (KO) mice had higher 5-oxoproline levels coupled to increased oxidative stress. Compared with wild-type (WT) littermates, KO mice had increased cardiac and renal fibrosis with concurrent elevated left ventricular (LV) filling pressures, impaired LV relaxation, yet a normal LV ejection fraction. Following the induction of cardiac ischaemia/reperfusion (IR) injury, 52.4% of the KO mice died compared with only 15.4% of the WT mice (P < 0.03). Furthermore, KO mice showed a significantly increased atrial, ventricular, kidney, and liver weights compared with WT mice (P < 0.05 for all). Cardiac...Continue Reading

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Citations

Sep 5, 2020·The Biochemical Journal·Anand K BachhawatPratiksha Dubey
Apr 2, 2020·Clinical Chemistry·Keito HoshitsukiPatricia J Barker
May 22, 2020·Clinical and Experimental Nephrology·Rena MiyakawaHideki Wakui
Jun 3, 2021·Journal of Clinical Medicine·Hiroshi SakagamiTakaaki Oizumi
Jul 3, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Andrea Del CampoHugo E Verdejo
Sep 1, 2021·Nature Communications·Niels Grote BeverborgPeter van der Meer
Dec 7, 2021·Frontiers in Nutrition·Kaitlin DayBarbara R Cardoso

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