Menopause causes arterial senescence and atherosclerotic development through decrease of estrogen. Recently, histone deacetylase SIRT1 has been reported to have protective effects against arterial senescence and atherosclerosis. However, the relationship between estrogen and SIRT1 in the context of menopause-induced arterial senescence is not well understood. The present study aims to investigate whether SIRT1 is involved in the etiology of menopause-induced arterial senescence and atherosclerotic development. Methods: Twelve-week old female apolipoprotein E-knockout (ApoE-KO) mice underwent ovariectomy (OVX) or sham surgery. Results: SIRT1 expression and endothelial nitric oxide synthase (eNOS) activation in the aorta were significantly lower in OVX mice than they were in sham mice (OVX vs. sham, n 5 per group). Senescence-associated-galactosidase activity, protein expression of Ac-p53 and PAI-1, and aortic atherosclerosis lesions were significantly greater in OVX mice than they were in sham mice. Administration of 17-estradiol (E2) for eight weeks to OVX mice restored aortic SIRT1 expression, activated eNOS, and retarded OVX-induced arterial senescence and atherosclerotic development (E2 vs. control, n 5 per group). The effects of E2 on SIRT1 upregulation, antisenescence and anti-atherosclerosis were attenuated by administration of a SIRT1 inhibitor, sirtinol. In vitro experiment using human endothelial cells demonstrated that E2 also increased SIRT1 expression and retarded oxidized low density lipoprotein-induced premature senescence, which were also abolished by sirtinol. These results suggested that estrogen modulated arterial senescence and atherosclerosis through SIRT1. Additionally a selective estrogen receptor modulator (SERM), bazedoxifene, also augmented SIRT1 and inhibited arterial senescence and atherosclerotic development (SERM vs. control, n 3 per group). Conclusions: Downregulation of SIRT1 causes OVX-induced arterial senescence and atherosclerosis in ApoE-KO mice. Administration of estrogen or SERM enables OVX mice to restore these alterations by SIRT1 induction. (age: 40, 40-44, 45-49, 50-54) 3). Therefore, it was expected that administration of estrogen might be able to prevent atherosclerotic development and reduce incidence of CVD. Indeed, animal experiments showed that female apolipoprotein E-knockout (ApoE-KO) mice subjected to ovariectomy (OVX) surgery reduced rates of atherosclerosis by administration of estrogen or 17-estradiol (E2), which is the primary hormone used in hormone replacement therapy (HRT) in postmenopausal women 4, 5). A recent

The elderly population is increasing because of increasing life expectancy, and the prevalence of frailty increases with age. Frailty commonly coexists with cardiovascular diseases (CVDs), such as coronary artery disease (CAD), heart failure (HF), aortic stenosis (AS), and atrial fibrillation (AF). Frail patients who undergo revascularization for CAD have higher complication rates; those with HF have a high prevalence of poor outcomes, and those with AF are vulnerable to increased stroke incidence. Moreover, frailty and asymptomatic severe AS were independent factors for mortality. The presence of frailty can lead to poor clinical outcomes, and frailty has been identified as a risk factor for mortality. Thus, the identification of frail patients who are at higher risks of disability and adverse clinical outcomes is important. In this review, the relationship between frailty and CVD is appraised and optimal treatments for frail patients are discussed.

Background The risk of cardiovascular disease is known to increase after menopause. Mitochondria, which undergo quality control via mitochondrial autophagy, play a crucial role in the regulation of cellular senescence. The aim of this study was to investigate whether the effect of estrogen‐mediated protection from senescence on arteries is attributed to the induction of mitochondrial autophagy. Methods and Results We used human umbilical vein cells, vascular smooth muscle cells, and 12‐week‐old female C57BL/6 mice. The administration of 17β‐estradiol (E2) to cells inhibited cellular senescence and mitochondrial dysfunction. Furthermore, E2 increased mitochondrial autophagy, maintaining mitochondrial function, and retarding cellular senescence. Of note, E2 did not modulate LC3 (light chain 3), and ATG7 (autophagy related 7) deficiency did not suppress mitochondrial autophagy in E2‐treated cells. Conversely, E2 increased the colocalization of Rab9 with LAMP2 (lysosomal‐associated membrane protein 2) signals. The E2‐mediated effects on mitochondrial autophagy were abolished by the knockdown of either Ulk1 or Rab9. These results suggest that E2‐mediated mitochondrial autophagy is associated with Rab9‐dependent alternative autophagy. E2 upregulated SIRT1 (sirtuin 1) and activated LKB1 (liver kinase B1), AMPK (adenosine monophosphate‐activated protein kinase), and Ulk1, indicating that the effect of E2 on the induction of Rab9‐dependent alternative autophagy is mediated by the SIRT1/LKB1/AMPK/Ulk1 pathway. Compared with the sham‐operated mice, ovariectomized mice showed reduced mitochondrial autophagy and accelerated mitochondrial dysfunction and arterial senescence; these detrimental alterations were successfully rescued by the administration of E2. Conclusions We showed that E2‐induced mitochondrial autophagy plays a crucial role in the delay of vascular senescence. The Rab9‐dependent alternative autophagy is behind E2‐induced mitochondrial autophagy.

The heart is dependent on ATP production in mitochondria, which is closely associated with cardiovascular disease because of the oxidative stress produced by mitochondria. Mitochondria are highly dynamic organelles that constantly change their morphology to elongated (fusion) or small and spherical (fission). These mitochondrial dynamics are regulated by various small GTPases, Drp1, Fis1, Mitofusin, and Opa1. Mitochondrial fission and fusion are essential to maintain a balance between mitochondrial biogenesis and mitochondrial turnover. Recent studies have demonstrated that mitochondrial dynamics play a crucial role in the development of cardiovascular diseases and senescence. Disruptions in mitochondrial dynamics affect mitochondrial dysfunction and cardiomyocyte survival leading to cardiac ischemia/reperfusion injury, cardiomyopathy, and heart failure. Mitochondrial dynamics and reactive oxygen species production have been associated with endothelial dysfunction, which in turn causes the development of atherosclerosis, hypertension, and even pulmonary hypertension, including pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Here, we review the association between cardiovascular diseases and mitochondrial dynamics, which may represent a potential therapeutic target.

Lectin-like oxidized low-density lipoprotein (ox-LDL) causes vascular senescence and atherosclerosis. It has been reported that ox-LDL scavenger receptor-1 (LOX-1) is associated with the angiotensin II type 1 receptor (AT1R). While mitochondria play a crucial role in the development of vascular senescence and atherosclerosis, they also undergo quality control through mitochondrial dynamics and autophagy. The aim of this study was to investigate (1) whether LOX-1 associates with AT1R, (2) if this regulates mitochondrial quality control, and (3) whether AT1R inhibition using Candesartan might ameliorate ox-LDL-induced vascular senescence. We performed in vitro and in vivo experiments using vascular smooth muscle cells (VSMCs), and C57BL/6 and apolipoprotein E-deficient (ApoE KO) mice. Administration of oxidized low-density lipoprotein (ox-LDL) to VSMCs induced mitochondrial dysfunction and cellular senescence accompanied by excessive mitochondrial fission, due to the activation of fission factor Drp1, which was derived from the activation of the Raf/MEK/ERK pathway. Administration of either Drp1 inhibitor, mdivi-1, or AT1R blocker candesartan attenuated these alterations. Electron microscopy and immunohistochemistry of the co-localization of LAMP2 with TOMM20 signal showed that AT1R inhibition also increased mitochondrial autophagy, but this was not affected by Atg7 deficiency. Conversely, AT1R inhibition increased the co-localization of LAMP2 with Rab9 signal. Moreover, AT1R inhibition-induced mitochondrial autophagy was abolished by Rab9 deficiency, suggesting that AT1R signaling modulated mitochondrial autophagy derived from Rab9-dependent alternative autophagy. Inhibition of the Raf/MEK/ERK pathway also decreased the excessive mitochondrial fission, and Rab9-dependent mitochondrial autophagy, suggesting that AT1R signaling followed the Raf/MEK/ERK axis modulated both mitochondrial dynamics and autophagy. The degree of mitochondrial dysfunction, reactive oxygen species production, vascular senescence, atherosclerosis, and the number of fragmented mitochondria accompanied by Drp1 activation were all higher in ApoE KO mice than in C57BL/6 mice. These detrimental alterations were successfully restored, and mitochondrial autophagy was upregulated with the administration of candesartan to ApoE KO mice. The association of LOX-1 with AT1R was found to play a crucial role in regulating mitochondrial quality control, as cellular/vascular senescence is induced by ox-LDL, and AT1R inhibition improves the adverse effects of ox-LDL.