Gas chromatography/time‐of‐flight mass spectrometry based metabonomic approach to differentiating hypertension‐ and age‐related metabolic variation in spontaneously hypertensive rats

Abstract

Metabonomics is a systematic approach to the study of in vivo metabolic profiles and therefore allows deep insight into and a better understanding of the pathogenesis of disease. To characterize the development of hypertension, a hypertensive animal model, the spontaneously hypertensive rat (SHR), and its normotensive control, the Wistar Kyoto (WKY) rat, were investigated and their blood plasma analyzed using the high-throughput metabolomic tool, gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). A total of 187 peaks were quantitatively determined after deconvolution, and 78 of them were identified. Principal components analysis (PCA) and projection to latent structure partial least-squares discriminant analysis (PLS-DA) were used to process the GC/TOFMS data. The resulting mathematical models were further validated by cross-validation. Plasma compositional differences of many identified compounds showed hypertension-related variation between SHR and WKY rats, and age-related changes from 10 to 18 weeks for both the SHR and WKY rats. These compositional changes involved compounds such as hexadecanoic acid, linoleic acid, oleic acid, stearic acid, 3-hydroxybutyric acid, citric acid, threonic acid, tyrosine, tryptophan, threonine, phenylalanine, serine, ornithine, methionine, 3-hydroxyproline, creatinine, erythrose, myo-inositol, D-methylglucopyranoside, tocopherol, sitosterol, and nonesterified cholesterol. Significantly elevated free fatty acids (FFA) were observed in SHR relative to those in WKY rats, and their levels increased as the SHR aged from 10 to 18 weeks. The close correlation between FFA and hypertension suggests that FFA are potential biomarker candidates for hypertension and they may play an important role in the development of hypertension in SHR. It is also indicated that GC/TOFMS-based metabonomics is a powerful approach to identifying potential biomarkers and investigating the pathological processes of hypertension and the physiological developments of aging.

Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats

“…The genome-wide mapping of human loci has linked many candidate genes to essential hypertension [6,7] , although none of them has been widely confirmed in different population groups. Recently, the metabolic profiling of hypertension has drawn the attention of researchers [8][9][10][11][12][13][14] . Brindle and colleagues found a relationship between serum metabolic profiles and blood pressure in clinic patients [9] .…”

“…Brindle and colleagues found a relationship between serum metabolic profiles and blood pressure in clinic patients [9] . Our previous studies of clinical patients and spontaneously hypertensive rats (SHRs) clearly showed that metabolomic patterns associated with hypertension were different from those of the normotensive controls, demonstrating the obviously perturbed metabolism of hypertension [12][13][14] . Hypertension is inherently involved in metabolic syndrome, including hyperlipidemia and diabetes.…”

“…The relationship between hypertension and metabolic disorders is of great interest. Unfortunately, although these studies have confirmed the metabolic perturbation underlying hypertension and underscore the potential of Differential regulations of blood pressure and perturbed metabolism by total ginsenosides and conventional antihypertensive agents in spontaneously hypertensive rats npg metabonomics to investigate the metabolic causes of hypertension, they have only investigated the hypertension and agerelated metabolic patterns of SHRs and the influence of total ginsenosides on those patterns [9,12,13] . There has been little exploration of metabolism in vivo or the regulatory effects of ginseng on metabolism.…”

Development of a serum profile for healthy aging

“…For example, genomic techniques recently were used to identify a genetic variation within the FOXO3A gene that is strongly associated with human longevity (Willcox et al 2008). Metabolomic techniques identified a close association between free-fatty acids and hypertension in the salt-dependent hypertensive rodent, suggesting that this powerful approach may be useful in identifying potential biomarkers of hypertension and the physiological consequences of aging (Lu et al 2008). …”

Chronic caloric restriction partially protects against age-related alteration in serum metabolome

“…This methodology has also been applied in aging studies in several species including Caenorhabditis elegans, fruit fly, rodents, dogs, and humans (Kristal and Shurubor 2005;Mishur and Rea 2012). In mammalian studies, carnitines, fatty acids, and other metabolites associated with energy metabolism, lipid metabolism, nucleic acid metabolism, and oxidative stress were shown to be perturbed with age (Williams et al 2005;Granger et al 2007;Lu et al 2008;Lawton et al 2008).…”