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.

Autor:	van der Pol A; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands.; Division of Perioperative Inflammation and Infection, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany., Gil A; Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands., Tromp J; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands.; National Heart Centre Singapore, Singapore, Singapore., Silljé HHW; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., van Veldhuisen DJ; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., Voors AA; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., Hoendermis ES; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., Grote Beverborg N; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., Schouten EM; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., de Boer RA; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands., Bischoff R; Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands., van der Meer P; Department of Cardiology, University Medical Center Groningen, University of Groningen, AV Groningen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2018 Dec 01; Vol. 114 (14), pp. 1871-1882.
DOI:	10.1093/cvr/cvy187
Abstrakt:	Aims: 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. Methods and Results: 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 and renal fibrosis were more pronounced following cardiac IR injury in the KO mice and these mice developed proteinuria post-IR injury. To further address the link between 5-oxoproline and HFpEF, 5-oxoproline was measured in the plasma of HFpEF patients. Compared with healthy controls (3.8 ± 0.6 µM), 5-oxoproline levels were significantly elevated in HFpEF patients (6.8 ± 1.9 µM, P < 0.0001). Furthermore, levels of 5-oxoproline were independently associated with more concentric remodelling on echocardiography. Conclusion: Oxidative stress induced by 5-oxoproline results in a murine phenotype reminiscent of the clinical manifestation of HFpEF without the need for surgical or pharmacological interference. Better understanding of the role of oxidative stress in HFpEF may potentially lead to novel therapeutic options.
Databáze:	MEDLINE
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