Establishment of the circadian metabolic phenotype strategy in spontaneously hypertensive rats: a dynamic metabolomics study

Abstract

Background: Circadian rhythms play a fundamental role in the progression of cardiovascular events. Almost all cardiovascular diseases have a circadian misalignment usually characterized by changes in metabolites. This study aimed to dynamically monitor rhythmic biomarkers, to elucidate the metabolic pathways that are potentially under circadian control in spontaneously hypertensive rats (SHRs), and to eventually establish a circadian metabolic phenotype strategy based on metabolomics. Methods: In this study, an untargeted metabolomics technology was used to dynamically monitor changes in serum metabolites between SHR model group and WKY control group. Liquid chromatography-mass spectrometry (LC-MS) combined with multivariate statistical analysis was applied to identify markers of hypertension rhythm imbalance. The concentrations of amino acids and their metabolites identified as markers were quantified by a subsequent targeted metabolomics analysis. Overall, these approaches comprehensively explored the rhythm mechanism and established a circadian metabolic phenotype strategy. Results: The metabolic profile revealed a disorder in the diurnal metabolism pattern in SHRs. Moreover, multivariate statistical analysis revealed metabolic markers of rhythm homeostasis, such as arginine, proline, phenylalanine, citric acid, l-malic acid, succinic acid, etc., accompanied by an imbalance in hypertension. The key metabolic pathways related to rhythm imbalance in hypertension were found by enrichment analysis, including amino acid metabolism, and the tricarboxylic acid cycle (TCA). In addition, the quantitative analysis of amino acids and their metabolites showed that the changes in leucine, isoleucine, valine, taurine, serine, and glycine were the most obvious. Conclusions: In summary, this study illustrated the relationship between metabolites and the pathways across time on hypertension. These results may provide a theoretical basis for personalized treatment programmes and timing for hypertension.

Gut microbiota steroid sexual dimorphism and its impact on gonadal steroids: influences of obesity and menopausal status

“…This could partly explain the substantial sex differences observed in hypertension from epidemiological studies [23]. Consistently, alterations in the arginine and proline metabolism have been reported in individuals at high risk of CVD [26] and spontaneously hypertensive rats [27]. We also found a consistent enrichment in the onecarbon pool by folate pathway in the microbiome of premenopausal women compared to post-menopausal women and men.…”

Plasma methionine metabolic profile is associated with longevity in mammals

“…Apart from lack-of-knowledge limitations, our work also has some technical limitations. First, the fact that although metabolome offers a wide amount of information, we cannot rule out the fact that plasma metabolome is highly affected by internal factors, such as tissue metabolism, or mixture of plasma with other biological fluids during animal sacrifice; and external factors, such as diet or circadian rhythms 80 , 81 . Nevertheless, we believe that these changes might be a reflection of individual or specimen-specific plasma metabolome modulations within a specie, and that the obtained plasma profile in our work reveals species-specific organismal metabolic adaptations associated to mammalian longevity.…”

Renal metabolism and hypertension

“…SS rats exhibit significant changes in plasma amino acid levels and skeletal muscle amino acid metabolism compared with SS.13 BN rats or in response to a high-salt diet, especially glycine, serine, and threonine metabolism and alanine, aspartate, and glutamate metabolism 93 , 109 . Serum levels of metabolites, including several amino acids and TCA cycle intermediates, have been reported to show circadian variation patterns that may be different between SHR and WKY rats 110 .…”