Aging, Arterial Stiffness, and Hypertension

Sun, Zhongjie

doi:10.1161/hypertensionaha.114.03617

Cited by 455 publications

(348 citation statements)

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“…Aging is associated with increased cardiovascular complications, such as arterial stiffness and hypertension (Sun, 2015). Arterial stiffness is an independent risk factor for myocardial infarction, cognitive decline in aging, stroke, and kidney diseases (Boutouyrie et al., 2002; Matsuoka et al., 2005; Waldstein et al., 2008; Zoungas & Asmar, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies showed that DNA methylation is increased with age (Alvares, Mayberry, Joyner, Lakowski & Ahmed, 2014; Avrahami et al., 2015; Bigot et al., 2015; Wagner et al., 2016; Zinovkina & Zinovkin, 2015). Coincidently, the prevalence of arterial stiffness and hypertension also increases with age (Sun, 2015). Arterial stiffening is an independent predictor of cardiovascular outcomes, such as hypertension, myocardial infarction, cognitive decline in aging, stroke, and kidney diseases (Hashimoto & Ito, 2011, 2013; Karras et al., 2012; Kitzman et al., 2013; Sun, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Coincidently, the prevalence of arterial stiffness and hypertension also increases with age (Sun, 2015). Arterial stiffening is an independent predictor of cardiovascular outcomes, such as hypertension, myocardial infarction, cognitive decline in aging, stroke, and kidney diseases (Hashimoto & Ito, 2011, 2013; Karras et al., 2012; Kitzman et al., 2013; Sun, 2015). However, the relationship of DNA methylation and aging‐related arterial stiffening is unclear.…”

Section: Introductionmentioning

confidence: 99%

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Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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Summary DNA methylation increases with age. The objective of this study was to investigate whether compound H, a potential activator of DNA demethylases, attenuates aging‐related arterial stiffness and hypertension. Aged mice (24–27 months) and adult mice (12 months) were used. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) were increased significantly in aged mice. Notably, daily treatments with compound H (15 mg/kg, IP) for 2 weeks significantly attenuated the aging‐related increases in PWV and BP. Compound H abolished aging‐associated downregulation of secreted Klotho (SKL) levels in both kidneys and serum likely by enhancing DNA demethylase activity and decreasing DNA methylation. Aging‐related arterial stiffness was associated with accumulation of stiffer collagen and degradation of compliant elastin which are accompanied by increased expression of MMP2, MMP9, TGF‐β1, and TGF‐β3. These changes were effectively attenuated by compound H, suggesting rejuvenation of aged arteries. Compound H also rescued downregulation of Sirt1 deacetylase, AMPKα, and eNOS activities in aortas of aged mice. In cultured smooth muscle cells (SMCc) Klotho‐deficient serum upregulated expression of MMPs and TGFβ which, however, was not affected by compound H. In conclusion, compound H attenuates aging‐associated arterial stiffness and hypertension by activation of DNA demethylase which increases renal SKL expression and consequently circulating SKL levels leading to activation of the Sirt1‐AMPK‐eNOS pathway in aortas of aged mice.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Chen

Sun

2018

Aging Cell

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“…The initial evidence of age‐related large arterial function decline is vascular wall thickening and loss of elasticity and distensibility 23, 2425.…”

Section: Discussionmentioning

confidence: 99%

Racial Differences in Arterial Stiffness are Mainly Determined by Blood Pressure Levels: Results From the ELSA‐Brasil Study

Baldo

Cunha

Ribeiro

et al. 2017

JAHA

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BackgroundBlack people have a higher risk of developing hypertension and presenting higher vascular stiffening. Our aim was to investigate whether the association between race and aortic stiffness could be explained by differences in the primary risk factors.Methods and ResultsWe analyzed data from 11 472 adults (mean age, 51.9±8.9; 53.8% female) self‐reported as white (n=6173), brown (n=3364), or black (n=1935). Their carotid‐to‐femoral pulse wave velocity (cf‐PWV) as well as clinical and anthropometric parameters were measured. cf‐PWV was higher in blacks than in whites or browns (men: white, 9.63±1.81; brown, 9.63±1.88; black, 9.98±1.99; women: white, 8.84±1.64; brown, 9.02±1.68; black, 9.34±1.91; P<0.05). However, this difference disappeared after adjustments for age, mean arterial pressure, heart rate, waist circumference, fasting glucose, and glomerular filtration rate (men: white, 9.68±1.54; brown, 9.68±1.50; black, 9.73±1.52; women: white, 8.93±1.32; brown, 8.98±1.29; black, 9.02±1.32; P>0.05). The association between race and arterial stiffness was significant for brown and black women in the highest cf‐PWV quartile, even after controlling for covariates. There were no differences in the age‐related increase in cf‐PWV among the racial groups after adjustment, confirming the strong effect of age and mean arterial pressure on cf‐PWV revealed by the multiple linear regression.ConclusionsRacial differences in cf‐PWV were mainly attributed to differences in mean arterial pressure and age, although they cannot fully explain the association between race and cf‐PWV in women in the highest cf‐PWV values. This suggests that therapeutic approaches to overcome the effects of aging on the vascular system should focus on blood pressure control, especially in the black population.

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“…In the clinical setting, aging‐related arterial stiffening24 promotes left ventricular hypertrophy (LVH) via complex interactions among elevated systemic blood pressure, increased pulse pressure, diminished arterial distensiblity, and augmented left ventricular (LV) afterload. This hemodynamic system, termed aortoventricular coupling (AVC), leads to LVH and diastolic dysfunction 25.…”

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confidence: 99%

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Ben‐Zvi

Savion

Kolodgie

et al. 2016

JAHA

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BackgroundAscending thoracic aortic aneurysm (ATAA) is driven by angiotensin II (AngII) and contributes to the development of left ventricular (LV) remodeling through aortoventricular coupling. We previously showed that locally available leptin augments AngII‐induced abdominal aortic aneurysms in apolipoprotein E–deficient mice. We hypothesized that locally synthesized leptin mediates AngII‐induced ATAA.Methods and ResultsFollowing demonstration of leptin synthesis in samples of human ATAA associated with different etiologies, we modeled in situ leptin expression in apolipoprotein E–deficient mice by applying exogenous leptin on the surface of the ascending aorta. This treatment resulted in local aortic stiffening and dilation, LV hypertrophy, and thickening of aortic/mitral valve leaflets. Similar results were obtained in an AngII‐infusion ATAA mouse model. To test the dependence of AngII‐induced aortic and LV remodeling on leptin activity, a leptin antagonist was applied to the ascending aorta in AngII‐infused mice. Locally applied single low‐dose leptin antagonist moderated AngII‐induced ascending aortic dilation and protected mice from ATAA rupture. Furthermore, LV hypertrophy was attenuated and thickening of aortic valve leaflets was moderated. Last, analysis of human aortic valve stenosis leaflets revealed de novo leptin synthesis, whereas exogenous leptin stimulated proliferation and promoted mineralization of human valve interstitial cells in culture.ConclusionsAngII‐induced ATAA is mediated by locally synthesized leptin. Aortoventricular hemodynamic coupling drives LV hypertrophy and promotes early aortic valve lesions, possibly mediated by valvular in situ leptin synthesis. Clinical implementation of local leptin antagonist therapy may attenuate AngII‐induced ATAA and moderate related LV hypertrophy and pre–aortic valve stenosis lesions.Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00449306.

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Aging, Arterial Stiffness, and Hypertension

Cited by 455 publications

References 48 publications

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Activation of DNA demethylases attenuates aging‐associated arterial stiffening and hypertension

Racial Differences in Arterial Stiffness are Mainly Determined by Blood Pressure Levels: Results From the ELSA‐Brasil Study

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

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