Abstract
Hypertension is caused by polygenic inheritance and the interaction of various environmental factors. Abnormal function of the renin-angiotensin-aldosterone system (RAAS) is closely associated with changes in blood pressure. As an essential factor in the RAAS, angiotensin II (Ang II) contributes to vasoconstriction and inflammatory responses. However, the effects of overproduction of Ang II on the whole body-metabolism have been unclear. In this study, we established a hypertensive mouse model by micro-osmotic pump perfusion of Ang II, and the maximum systolic blood pressure reached 140 mmHg after 2 weeks. By ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, the metabolites in the serum of hypertensive model and control mice were analyzed. Partial least squares discriminant analysis (PLS-DA) in both positive and negative ionization modes showed clear separation of the two groups. Perfusion of Ang II induced perturbations of multiple metabolic pathways in mice, such as steroid hormone biosynthesis and galactose metabolism. Tandem mass spectrometry revealed 40 metabolite markers with potential diagnostic value for hypertension. Our data indicate that non-targeted metabolomics can reveal biochemical pathways associated with Ang II-induced hypertension. Although researches about the clinical use of these metabolites as potential biomarkers in hypertension is still needed, the current study improves the understanding of systemic metabolic response to sustained release of Ang II in hypertensive mice, providing a new panel of biomarkers that may be used to predict blood pressure fluctuations in the early stages of hypertension.
Highlights
Hypertension is a common cardiovascular disease and the leading risk factor for both cardiovascular and cerebrovascular events
All animal experiments were performed in accordance with the laboratory animal guidelines and with the approval of the Abbreviations: RAAS, renin-angiotensin-aldosterone system; Ang II, angiotensin II; UPLC-Q-TOF/MS, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry; LC-MS, liquid chromatography-mass spectrometry; QC, quality control; ESI+, electrospray ionization positive ion mode; ESI, electrospray ionization negative ion mode; RSD, relative standard deviation; PCA, principal component analysis; Partial least squares discriminant analysis (PLS-DA), partial least squaresdiscriminant analysis; ABC, ATP binding cassette membrane transporter; peroxisome proliferator-activated receptor (PPAR), peroxisome proliferators-activated receptor
Volcano maps based on P-values and one-dimensional test multiple changes (Figures 3C,D) and heat maps based on differences in metabolite abundance showed clear separation of the Ang II and control groups (Figures 3E,F)
Summary
Hypertension is a common cardiovascular disease and the leading risk factor for both cardiovascular and cerebrovascular events. It can cause functional or organic lesions of the heart, brain, blood vessels, kidneys, and other organs, contributing to a significant cause of disability and death [1]. Ang II increases systemic blood pressure and glomerular capillary pressure It is directly involved in renal arteriosclerosis and causes kidney damage [4]. It increases the pressure in the glomeruli and contracts mesangial cells, leading to an increase in the selective permeability to urine proteins. Ang II-induced hypertension leads to the hypertrophy of smooth muscle cells and to increases in the expression of their specific markers, eventually leading to thickening of the arterial media and increasing vascular resistance [7]
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