Review articleEndothelium-specific CYP2J2 overexpression improves cardiac dysfunction by promoting angiogenesis via Jagged1/Notch1 signaling
Graphical abstract
Introduction
Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide and is a worsening public health problem [1,2]. During MI, inadequate blood flow to an ischemic heart muscle leads to cardiomyocytes death and pathological remodeling, which head to heart failure over time [3,4]. Although ischemia induces endogenous myocardial angiogenesis, this process is insufficient for maintaining a normal myocardial blood supply. The application of advanced revascularization strategies, such as primary percutaneous coronary intervention (PCI) and surgical bypass, have led to a remarkable decrease in mortality rates. However, these strategies have inherent limitation, such as the ‘no-reflow’ phenomenon. In addition, a large proportion of patients with MI who received these treatments showed inadequate myocardial perfusion, owing to dysfunction of the microcirculation or lack of myocardial angiogenesis [5]. Hence, therapeutic angiogenesis which aims to restore blood flow to the ischemic myocardial zone is considered as a promising treatment to salvage ischemic myocardium and prevents the transition to heart failure.
The term“angiogenesis” refers to the process of blood vessels formation from pre-existing vascular bed [6], angiogenic growth factors act as fundamental role in this process. Vascular endothelial growth factor A (VEGF-A) and basic fibroblast growth factor (bFGF) are the major and well-studied growth factors in ischemic tissues among the current known pro-angiogenic growth factors [7]. VEGF-A can initiate multiple signaling pathways that orchestrate a variety of complex biological effects, such as endothelial cells maturation, angiogenesis and arteriogenesis in response to hypoxia or healing, and it stimulates angiogenesis through vascular endothelial growth factor receptor-2 (VEGFR2) signaling mainly [8].
Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid (AA) to four biologically and cardioprotective epoxyeicosatrienoic acids (EETs): 5, 6-EET, 8, 9-EET, 11, 12-EET, and 14, 15-EET. The primary products are 11, 12- and 14, 15-EET. Via the activity of soluble epoxide hydrolase (sEH), EETs are metabolized to dihydroxyeicosatrienoic acid (DHET), a compound that is more stable and less bioactive [9]. The human cytochrome P450 epoxygenase, CYP2J2, is the only member of the human CYP2J family, which expresses abundantly in coronary artery endothelial cells, smooth muscle cells, and cardiomyocytes [[10], [11], [12]]. CYP2J2 and EETs have pleotropic effects in cardioprotection, including alleviating inflammatory reactions [13], inhibiting apoptosis [14], and attenuating cardiac remodeling and hypertrophy [15,16]. Previous studies also revealed that cardiac-specific overexpression of human CYP2J2 or EETs administration directly enhanced cardiac recovery of left ventricular function during ischemia/reperfusion involved activation of p42/p44-MAPK signaling pathway [17,18]. However, these studies mainly focused the cardioprotection of CYP2J2 and EETs on cardiomyocytes, little was known about the cardioprotection on endothelial cells-induced angiogenesis. Vascular endothelial cells play a prominent role in cardiovascular physiology and pathobiology. Recent studies have gradually recognized the crucial role of endothelium-specific CYP2J2 overexpression in ischemia disease [19,20]. Thus, the present study demonstrated that endothelium-specific CYP2J2 overexpression protected against post-MI heart failure in rats, and this cardioprotective role was associated with increasing the level of circulating EETs and promoting angiogenesis via Jaggged1/Notch1 signaling.
Section snippets
Origin of human heart samples
Human heart tissue samples diagnosed with MI were obtained from patients who underwent cardiac transplantation in our hospital, Union Hospital (Wuhan, China) and organ donors from 2013―2016. Control hearts were obtained from sex- and age-matched subjects who died in traffic accidents or had been diagnosed with aortic regurgitation. These patients did not have ischemic heart diseases, their family members donated their organs voluntarily. The study was approved by the Ethics Review Board of
RNA interference
The small interfering RNA (siRNA) oligonucleotides of Notch1 and the corresponding control were synthesized by RuiBo (China). Transfection was performed when HUVECs reached the density of approximately 30%―40% confluent. HUVECs were transfected with the siRNA of Notch1 using Lipofectamine2000 (Invitrogen, USA) 48 h prior to treatment with the scheduled conditions. The siRNA was diluted to a final concentration of 50 nM in Opti-Mem I (Invitrogen). After that, transfection reagent (Invitrogen,
CYP2J2 and sEH expression are up-regulated in patients with heart failure post MI
We detected CYP2J2 and sEH protein and messenger RNA expression in human heart samples (Information pertaining to these heart samples is presented in Supplementary Table S1). Western blot analysis showed that CYP2J2 expression was upregulated clearly in patients with AMI and OMI, compared to control patients (Fig. 1A and B). Interestingly, sEH expression tended to be increased in patients with AMI, while did not alter in patients with OMI, compared control patients (Fig. 1A and C). Next, qPCR
Discussion
The main finding of our work is that endothelium-specific CYP2J2 overexpression favourably affects the performance of failing hearts (as evaluated by echocardiography and cardiac catheterization). Specifically, CYP2J2 overexpression improved the LV ejection fraction and lowered LV wall stress. We also demonstrated that gain-of-function in CYP2J2 decreased mortality rates and attenuated LV remodeling, as assessed by analyses of fibrosis, LV wall thickness, and HW-to-BW ratios. These effects were
Sources of funding
This research was supported by the following grants: NIH 31130031 and NIH 91439203.
Acknowledgements
We are grateful to Riverine Technology Co., Ltd. (Wuhan, China) for providing technical assistance with the small-animal PET imaging analysis. We thank the Department of Pulmonary and Critical Care Medicine (TongJi Hospital, TongJi Medical College, Huazhong University of Science and Technology) for providing three gas incubator and thank Department of Physiology and Tianjin Medical University (Tianjin, China) for performing LC/MS/MS analysis.
Nonstandard abbreviations and acronyms
- MI
Myocardial infarction
- HF
Heart failure
- EETs
Epoxyeicosatrienoic acids
- CYP
Cytochrome P450
- sEH
Soluble epoxide hydrolase
- AMI
Acute myocardial infarction
- OMI
Old myocardial infarction
- TG
Transgenic
- WT
Wild-type
- VEGF
Vascular endothelial growth factor
- PET
Positron emission computed tomography
- IZ
Infarct Zone
- BZ
Border Zone
- RZ
Remote Zone
- LC/MS/MS
Liquid chromatography tandem mass spectroscopy
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These authors contributed equally to this work.