Lifelong dietary omega-3 fatty acid reverses cardiac and vascular dysfunction via MMP-2 modulation in aged mice

Abstract

Background Aging has a remarkable effect on the cardiovascular system, and negatively causes structural and functional changes in the heart including diastolic/systolic dysfunction and left ventricular (LV) dyssynchrony, as well as, arterial stiffness which may develop to heart failure with preserved ejection fraction (HFpEF) in aged adults. We recently showed that the plant-derived omega-3-fatty-acid α-linolenic-acid (ALA) has emerged to confer potential protective effects against cardiovascular disease. Since cardiovascular aging is a chronic process, we hypothesized that a lifelong effective dietary supplementation with ALA will reverse or prevent age-related diastolic and arterial dysfunction during aging. Purpose Here, we test the hypotheses that (1) lifelong dietary ALA will prevent LV diastolic and arterial dysfunction in aged mice and that (2) lifelong dietary ALA will prevent the age-related cardiovascular dysfunction through modiulation of matrix-metalloproteinase-2 (MMP-2) in the heart and arteries. Methods and results 6-month-old (young) wild-type C57BL/6J mice were fed a low (0.03%), as control, or high ALA (7.3%) diet for more than 12 months. Our results show that aged (>18 months) mice on low ALA diet recapitulate major hallmarks of HFpEF, including diastolic dysfunction with preserved left ventricular ejection fraction, cardiac interstitial fibrosis, impaired acetylcholine-induced relaxation of aortic segments, and arterial stiffness. Intriguingly, we revealed that lifelong ALA-rich diet prevents diastolic dysfunction, vascular relaxation capacity, reduced pulse wave velocity, interstitial fibrosis, and coincident hemodynamic abnormalities in aged mice. Lifelong dietary ALA-in the prevention strategy-was associated with remarkably reduced cardiac and aortic MMP-2 and COX-2 expression, lower levels of pro-inflammatory cytokine TNF-α, and increased isocitrate dehydrogenase 2 (Idh2) expression, decreased function of which has previously been associated with cardiac dysfunction. Conclusions Our data support that lifelong ALA-rich diet restores normal cardiac and vascular function in aged mice with LV diastolic and arterial dysfunction and prevents development of age-related cardiovascular dysfunction through the modulation of MMP-2 signaling. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): 1. Swiss National Science Foundation (number 324730_182328)2. the Kardio Stiftung, Baden, Switzerland

Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging

“…Acetate could also regulate epigenetic-SASP interplay in PAA-treated ECs, where it downregulates VCAM1 and alleviates endothelial dysfunction. As we and others exhibited, IL6 underlies vascular premature aging and atherosclerotic CVD 24 , whereas acetate at least in HUVEC can inhibit the production of IL-6 and IL-8 and subsequently reduce VCAM1mediated cell adhesion 51 . In line with this, our findings revealed that acetate, by downregulating IL6-CaMKII, reduces HDAC4 S632 phosphorylation and stabilizes its nuclear localization, which thereby decreases VCAM1 expression.…”

“…3e). Since glutathione peroxidase converts oxidized glutathione (GSSG) to its reduced form (GSH), a key cellular ROS-scavenger 24 , we measured GPx1 transcriptional levels in baseline conditions and upon exposure to exogenous PAA (as "stress condition"). Levels of Gpx1 transcripts showed a significant reduction in PECs in stress condition induced by PAA, supporting a role of PAA in counteracting simultaneous antioxidant defense and inducing oxidative stress (Supplementary Fig.…”

“…By excessive ROS production, particularly H 2 O 2 , in the mitochondria of PECs, PAA induces the expression of these CDK inhibitors and increases SA-β-galactosidase activity and DNA damage response (represented by increased γ-H2A.X), and thereby promotes EC senescence. Aside from this, PAA-induced stress condition counteracts ROS-scavenging system including GPx1, which converts oxidized glutathione (GSSG) to its reduced form (GSH), in PECs 24 . These data are consistent with what observed in oxidized low-density lipoprotein (oxLDL)-induced senescent HUVEC endothelial cells 37 , in which glutathione peroxidase decline has been associated with a dramatic activation of p53/p21 pathway and subsequent endothelial dysfunction, proven as subclinical stage of atherosclerosis 38 .…”

Targeting the redox system for cardiovascular regeneration in aging

“…Accordingly, diabetic cardiomyopathy has been considered as a cardiac disease of aging, and its development and progression has been strongly associated with accelerated ROS‐induced oxidative stress and mitochondrial dysfunction in cardiac cells (Kayama et al., 2015). Combined relatively low endogenous antioxidant capacity and increased ROS levels in the heart has been also observed in heart failure with preserved ejection fraction (HFpEF), which comprises >50% of all HF cases worldwide (Jasinska‐Piadlo & Campbell, 2023; Saeedi Saravi et al., 2023). In diabetic patients, circulating high glucose and altered insulin signaling are associated with increased ROS generation and susceptibility to oxidative responses in the heart, leading to tissue remodeling, ventricular hypertrophy, and impaired systolic and diastolic function (Huo et al., 2023; Nishio et al., 2004).…”