Abstract
While aging is a critical risk factor for heart failure, it remains uncertain whether the aging heart responds differentially to a hypertensive stimuli. Here we investigated phenotypic and transcriptomic differences between the young and aging heart using a mineralocorticoid-excess model of hypertension. Ten-week (“young”) and 36-week (“aging”) mice underwent a unilateral uninephrectomy with deoxycorticosterone acetate (DOCA) pellet implantation (n = 6–8/group) and were followed for 6 weeks. Cardiac structure and function, blood pressure (BP) and the cardiac transcriptome were subsequently examined. Young and aging DOCA mice had high BP, increased cardiac mass, cardiac hypertrophy, and fibrosis. Left ventricular end-diastolic pressure increased in aging DOCA-treated mice in contrast to young DOCA mice. Interstitial and perivascular fibrosis occurred in response to DOCA, but perivascular fibrosis was greater in aging mice. Transcriptomic analysis showed that young mice had features of higher oxidative stress, likely due to activation of the respiratory electron transport chain. In contrast, aging mice showed up-regulation of collagen formation in association with activation of innate immunity together with markers of inflammation including cytokine and platelet signaling. In comparison to younger mice, aging mice demonstrated different phenotypic and molecular responses to hypertensive stress. These findings have potential implications for the pathogenesis of age-related forms of cardiovascular disease, particularly heart failure.
Highlights
One of the major and most inevitable risk factor for the development of heart failure is aging, when combined with hypertension (Owan et al, 2006)
To understand the molecular mechanisms involved in the increase in cardiac fibrosis and worsening of the deoxycorticosterone acetate (DOCA) phenotype with aging, we examined the cardiac transcriptome between young and aging sham and DOCA (n = 6 young sham, others n = 4 per group)
Overall in aging DOCA we observed a significant increase in pathways for collagen formation and apoptosis, an enrichment of the innate immune system, inflammasomes, and platelet activation, signaling and aggregation (Supplementary Table S6)
Summary
One of the major and most inevitable risk factor for the development of heart failure is aging, when combined with hypertension (Owan et al, 2006). The prevalence of heart failure has increased in the past decade, and is estimated to rise by 46% by 2030 (Benjamin et al, 2017). The prevalence of heart failure with preserved ejection fraction (HFPEF) is projected to rise significantly over the coming decade (Dunlay et al, 2017). While the role of aging per se as a cause of heart failure is unclear, the addition of risk factors such as hypertension is wellknown to be involved in the development of the disease (Dunlay et al, 2017)
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