Age- and sex-dependent alteration of functions and epigenetic modifications of vessel and endothelium related biomarkers

Abstract

Aging is a main risk factor for development of cardiovascular diseases associated with the impairment of endothelial function in both sexes. In the present study, age-related changes in vascular responsiveness, epigenetic modifications of vessel wall, and blood biomarkers related to endothelial functions were examined in an age- and sex-dependent manner. Acetylcholine (ACh)-induced relaxations of the aorta were decreased in 3-, 6-, and 12-month-old rats compared to those in 1-month-old female rats. In males, maximum relaxations related to ACh were higher in 1- and 6-month-old rats than in 3- and 12-month-old rats. Plasma levels of nitric oxide (NO) and asymmetric dimethylarginine (ADMA) decreased with age in female rats, and total antioxidant capacity (TAC) and hydrogen sulfide (H 2S) levels displayed biphasic alterations. In male rats, plasma levels of NO, TAC, and ADMA decreased with age, and H2S levels increased. Aging also caused a sex-dependent alteration in epigenetic modification of vessels. Expressions of H3K27me2, H3K27me3, H3K36me2, and H3K36me3 were much higher in vessels of 12-month-old female rats compared to those in younger age groups. These results indicate that vascular functions, epigenetic modifications of vessels, and plasma levels of endothelium-related biomarkers are affected by age and sex. These findings could be important for the assessment of vascular status over the course of the life span.

Keywords: Aging; biomarker; endothelial function; histone methylation.

Figure 1

Endothelium-dependent relaxation of thoracic aorta isolated from 1-, 3-, 6-, and 12-month-old female and male rats. ACh-induced endothelium-dependent relaxations were different in the female and male rats (P < 0.05). Differences at 1 month old (*), 6 months old (#), and 12 months old (+). Vasorelaxant responses are expressed as a percentage of submaximal contraction to phenylephrine (10–6 M). Values are expressed as mean ± SEM (n = 7–12).

Figure 2

KCl (90 mM)-stimulated contraction of the thoracic aorta isolated from 1-, 3-, 6-, and 12-month-old female and male rats. Contractions to KCl were similar in all female groups. In male rats, contractions increased with age (P < 0.05). Contractions were different in the female and male groups at the age of 1, 3, and 12 months old (P < 0.05). Differences from the same age female group (#). Values are expressed as mean ± SEM (n = 7–12).

Figure 3

Changes in plasma NO, ADMA, TAC, and H2S levels of 1-, 3-, 6-, and 12-month-old female and male rats. Differences from the same age female group (#) (P < 0.05). Values are expressed as mean ± SEM (n = 7–12).