Short reportHesperidin reverses perivascular adipose-mediated aortic stiffness with aging
Introduction
Aging is the major risk factor for cardiovascular disease (CVD) risk with nearly 70% of adults older than 60 years of age having at least one form of CVD (Writing Group et al., 2016). As such, aging has detrimental effects on arteries and arterial function leading to increased CVD risk (Lakatta and Levy, 2003). A key consequence of arterial aging is aortic stiffness, which is an independent predictor of cardiovascular events as assessed by aortic pulse wave velocity (aPWV) (Mitchell et al., 2010). Notably, aortic perivascular adipose tissue (PVAT) is associated with increased arterial stiffening and incident CVD (Britton et al., 2013a, Britton et al., 2013b), and has also been shown to promote aortic stiffness in animal models of aging and disease (Du et al., 2015, Fleenor et al., 2014). Age-related aortic stiffness is due, in part, to accumulation of advanced glycation end products (AGE). Importantly, AGE activates the nuclear factor-kappa B (NF-κB) signaling and increases oxidative stress (Schmidt et al., 1994, Yan et al., 1994) that, in turn, contributes to arterial stiffness (Wells-Knecht et al., 1996). It is unknown, however, if age-related increases of AGE within PVAT contributes to the stiffening process.
Developing novel interventions to reduce aortic stiffness and thereby attenuating CVD risk are clinically relevant. Hesperidin is a flavonoid naturally occurring in many fruits and vegetables (Kakadiya et al., 2010, Wilmsen et al., 2005). Importantly, increased dietary hesperidin intake from fruits and vegetables is associated with reduced CVD events and CVD-related mortality (Cassidy et al., 2012), suggesting the potential of hesperidin to reduce aortic stiffness and CVD risk with aging. Notably, hesperidin has been shown to improve endothelial function, a key contributor to arterial stiffness, and reduce AGE accumulation in experimental models of disease (Rizza et al., 2011, Shi et al., 2012). Currently, however, it is unknown if hesperidin reverses age-related aortic stiffness and PVAT AGE accumulation, or if AGE within PVAT promotes aortic stiffening.
The purpose of this investigation was to determine the effects of hesperidin on age-related aortic stiffness and PVAT AGE accumulation, and to also assess the effects of AGE within PVAT on aortic stiffening. We, therefore, hypothesized age-related aortic stiffness mediated by PVAT and AGE accumulation within this fat depot would be reversed by a 4-week hesperidin intervention. In addition, we hypothesized the AGE inhibitor, aminoguanidine (AMG), would reverse age-related aortic stiffness mediated by PVAT.
Section snippets
Animals
Young (6 months) and old (27–29 months) C57BL/6 mice were acquired from The Jackson Laboratory or the National Institute on Aging aged rodent colony at Charles River Laboratories, respectively. All mice were housed in a 12:12 h light:dark cycle animal facility on the University of Kentucky campus having ad libitum access to diet and water. Four groups of animals were studied: young control (N = 5), old control (N = 4), old hesperidin treated (N = 4) and old aminoguanidine (AGE inhibitor; AMG) treated (N =
Effects of hesperidin on aortic stiffness
Arterial stiffness assessed by aPWV (Fig. 1A) (P < 0.05) and ex vivo mechanical properties testing (Fig. 1B) (P < 0.05) were both greater in old compared with young control animals. The four-week hesperidin and AMG treatment in old mice reversed both aPWV and intrinsic mechanical stiffness to young control values (Fig. 1A and B) (P < 0.05, both). Heart rate acquired during aPWV was not different between groups (Young: 463 ± 19; Old: 451 ± 8; Old hesperidin: 441 ± 32; Old AMG: 485 ± 22 bpm; P > 0.05).
Influence of hesperidin on PVAT-mediated aortic stiffness and AGE accumulation
Mechanical
Discussion
Elucidating novel therapeutic interventions and identifying potential mechanisms of action that decrease age-related aortic stiffness and, therefore, reduce CVD risk are clinically significant. As such, our findings provide initial evidence for hesperidin to reverse: 1) aortic stiffness associated with aging; 2) PVAT mediated arterial stiffness and AGE accumulation; and, 3) PVAT-mediated aortic inflammation and oxidative stress. Additionally, our data reveals a novel effect of PVAT AGE
Conclusion
In summary, our findings provide novel evidence for hesperidin to reverse age-related aortic stiffness, PVAT-mediated arterial stiffening and PVAT AGE accumulation. Moreover, greater AGE abundance in PVAT promotes aortic stiffness, which is reduced with hesperidin and is associated with de-stiffening effects of this novel citrus-derived compound. Thus, these preclinical data provide insight for hesperidin as a novel, potentially translatable intervention to de-stiffen the aorta and reduce CVD
Conflict of interest
Dr. Fleenor, serving as principal investigator, has had funding from Astra Zeneca to study Saxagliptin.
Acknowledgements
Research reported in this publication was supported, in part, by National Institute of General Medicine Sciences Institutional Development Award 8-P20-GM-103527-05, and by University of Kentucky research funds.
References (20)
- et al.
Body fat distribution, incident cardiovascular disease, cancer, and all-cause mortality
J. Am. Coll. Cardiol.
(2013) - et al.
Sodium nitrite de-stiffening of large elastic arteries with aging: role of normalization of advanced glycation end-products
Exp. Gerontol.
(2012) - et al.
Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers
Am. J. Clin. Nutr.
(2011) - et al.
Alagebrium in combination with exercise ameliorates age-associated ventricular and vascular stiffness
Exp. Gerontol.
(2012) - et al.
Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins
J. Biol. Chem.
(1994) - et al.
Thoracic periaortic and visceral adipose tissue and their cross-sectional associations with measures of vascular function
Obesity (Silver Spring)
(2013) - et al.
Dietary flavonoids and risk of stroke in women
Stroke
(2012) - et al.
Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice
Am. J. Physiol. Heart Circ. Physiol.
(2015) - et al.
Superoxide-signaling in perivascular adipose tissue promotes age-related artery stiffness
Aging Cell
(2014) - et al.
Protective effect of hesperidin on cardiovascular complication in experimentally induced myocardial infarction in diabetes in rats
Journal of basic and clinical pharmacy
(2010)
Cited by (20)
Perivascular fat tissue and vascular aging: A sword and a shield
2024, Pharmacological ResearchPerivascular adipose tissue-mediated arterial stiffening in aging and disease: An emerging translational therapeutic target?
2022, Pharmacological ResearchCitation Excerpt :One such approach is to utilize nutraceuticals, or active ingredients in foods or extracted from foods that have health and/or medicinal effects, to change PVAT phenotype and lower arterial stiffness. Hesperidin, a flavonoid found in fruits and vegetables is one such compound that has been shown to reverse PVAT-mediated aortic stiffness that was associated with reductions in PVAT AGE [12]. This compound is currently investigational but has potential to be translated to human populations.
The Putative Role of Methylglyoxal in Arterial Stiffening: A Review
2021, Heart Lung and CirculationCitation Excerpt :Therefore, the observed stiffening effect of PVAT may be attributable, at least partly, to a PVAT-derived IL-6 induced increase in AGEs. PVAT-induced arterial stiffness was also observed in young compared to old C57BL/6 mice [30]. Administration of hesperidin and aminoguanidine ameliorated the age-dependent increase in aortic stiffness as well as the PVAT-mediated effects.
Enhanced antioxidant, anti-inflammatory and α-glucosidase inhibitory activities of citrus hesperidin by acid-catalyzed hydrolysis
2021, Food ChemistryCitation Excerpt :Hesperidin (HDN), as one of the richest flavonoids, is abundant in young citrus fruits (about 20% vs. DW) and the peel of mature ones (about 5% vs. DW). It was reported to exert a wide range of pharmacological effects, including antioxidant, anti-inflammation (Li, Lin, Lu, Zhou, & Luo, 2016), anticardiovascular (Ouyang, Garner, & Fleenor, 2017) and anticancer effects (Donia, Gerges, & Mohamed, 2018; Cincin, Kiran, Baran, & Cakmakoglu, 2018), etc. HDN is also one of the primary constituents of some traditional Chinese medicines, such as dried tangerine or orange peel (McGettrick, & O'Neill, 2013) and Fructus Aurantii (Xia, Wang, Ren, Li, Lu, & Zheng, 2018).
Adipose tissue as a possible therapeutic target for polyphenols: A case for Cyclopia extracts as anti-obesity nutraceuticals
2019, Biomedicine and Pharmacotherapy