1,721,138 research outputs found
Longevity-associated variant BPIFB4 gene transfer to recapitulate healthy ageing in patients at risk: is the future around the corner?
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Enhanced age-dependent cerebrovascular dysfunction is mediated by adaptor protein p66Shc
No full textBACKGROUND: Aging is an independent risk factor for cardiovascular and cerebrovascular disease. To date, little is known about the mechanisms of aging of cerebral arteries and whether the aging gene p66(Shc) is implicated in it. The present study was designed to assess age-induced vascular dysfunction in cerebral and systemic arteries of wild type (wt) and p66(Shc-/-) mice.
METHODS: Basilar arteries and size matched second order femoral arteries of 3-month (3M), 6-month (6M) and 2-year old (2Y) mice were studied in wt and p66(Shc-/-) mice. To assess vascular function, arterial rings mounted in a myograph for isometric tension recordings were exposed to increasing concentrations of acetylcholine and sodium nitroprusside. Reactive oxygen species (ROS) generation was assessed in femoral and basilar arteries using the spin trap 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine.
RESULTS: In wt mice, endothelial function of the femoral artery was not affected by age unlike in the basilar artery where an age-dependent dysfunction was observed. In p66(Shc-/-) a similar response was observed in the femoral artery; however, age-dependent endothelial dysfunction of the basilar artery was blunted as compared to wt. Levels of ROS were comparable in the femoral arteries of 3M and 2Y of wt and p66(Shc-/-) mice. Differently, ROS levels in the basilar artery of wt mice were strongly increased by age unlike in p66(Shc-/-) mice where they remained comparable irrespective of age.
CONCLUSIONS: Endothelial function in cerebral arteries, but not in size-matched systemic ones, is heavily impaired by aging. This process is paralleled by an increased ROS production and is mediated by the p66(Shc) gene
IL-1β and Statin Treatment in Patients with Myocardial Infarction and Diabetic Cardiomyopathy
Full text linkStatins are effective lipid-lowering drugs with a good safety profile that have become, over the years, the first-line therapy for patients with dyslipidemia and a real cornerstone of cardiovascular (CV) preventive therapy. Thanks to both cholesterol-related and "pleiotropic" effects, statins have a beneficial impact against CV diseases. In particular, by reducing lipids and inflammation statins, they can influence the pathogenesis of both myocardial infarction and diabetic cardiomyopathy. Among inflammatory mediators involved in these diseases, interleukin (IL)-1β is a pro-inflammatory cytokine that recently been shown to be an effective target in secondary prevention of CV events. Statins are largely prescribed to patients with myocardial infarction and diabetes, but their effects on IL-1β synthesis and release remain to be fully characterized. Of interest, preliminary studies even report IL-1β secretion to rise after treatment with statins, with a potential impact on the inflammatory microenvironment and glycemic control. Here, we will summarize evidence of the role of statins in the prevention and treatment of myocardial infarction and diabetic cardiomyopathy. In accordance with the dual lipid-lowering and anti-inflammatory effect of these drugs and in light of the important results achieved by IL-1β inhibition through canakinumab in CV secondary prevention, we will dissect the current evidence linking statins with IL-1β and outline the possible benefits of a potential double treatment with statins and canakinumab
Ageing and longevity genes in cardiovascular diseases
No full textOver the last century, Western societies experienced a demographic shift driven by increased lifespan and decreased fertility, resulting in the subversion of the world's demographic pyramid. In ageing societies, cardiovascular diseases are the major cause of morbidity and mortality, thus representing a major societal and economic burden. Indeed, ageing associates with the deterioration of a genetic network implicated in senescence and longevity, orchestrating deleterious cellular processes that converge in the structural and functional decline of both the myocardium and the vasculature. In this review, we revise a compendium of genes involved in these processes and delineate possible strategies to interfere with them. Dietary interventions (eg intermittent fasting) and sirtuin-activating compounds are among the most promising interventions shown to promote protective effects on the ageing cardiovascular system. We conclude that ageing and longevity genes modulate cardiovascular function by acting on deleterious downstream processes such as inflammation and oxidative stress, thus representing promising targets for the prevention and treatment of age-related cardiovascular dysfunction
Modern Concepts in Cardiovascular Disease: Inflamm-Aging
No full textThe improvements in healthcare services and quality of life result in a longer life expectancy and a higher number of aged individuals, who are inevitably affected by age-associated cardiovascular (CV) diseases. This challenging demographic shift calls for a greater effort to unravel the molecular mechanisms underlying age-related CV diseases to identify new therapeutic targets to cope with the ongoing aging "pandemic". Essential for protection against external pathogens and intrinsic degenerative processes, the inflammatory response becomes dysregulated with aging, leading to a persistent state of low-grade inflammation known as inflamm-aging. Of interest, inflammation has been recently recognized as a key factor in the pathogenesis of CV diseases, suggesting inflamm-aging as a possible driver of age-related CV afflictions and a plausible therapeutic target in this context. This review discusses the molecular pathways underlying inflamm-aging and their involvement in CV disease. Moreover, the potential of several anti-inflammatory approaches in this context is also reviewed
SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits
No full textAn increasing number of individuals is at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and premature death. The sodium-glucose cotransporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption, and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated view on the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With robust trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (ie, at cardiac, vascular, renal, and systemic levels), we provide insights into key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of vascular inflammation, oxidative stress, cellular energy metabolism and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrythmias are presented, and potential implications for future research and clinical practice are comprehensively reviewed
Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease
No full textThe ongoing worldwide increase in life expectancy portends a rising prevalence of age-related cardiovascular (CV) diseases in the coming decades that demands a deeper understanding of their molecular mechanisms. Inflammation has recently emerged as an important contributor for CV disease development. Indeed, a state of chronic sterile low-grade inflammation characterizes older organisms (also known as inflamm-ageing) and participates pivotally in the development of frailty, disability, and most chronic degenerative diseases including age-related CV and cerebrovascular afflictions. Due to chronic activation of inflammasomes and to reduced endogenous anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, endothelial, and vascular smooth muscle cells, thus accelerating vascular ageing and atherosclerosis. Furthermore, inflamm-ageing promotes the development of catastrophic athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for health care systems worldwide. Here, we discuss recent findings in the pathophysiology of inflamm-ageing, the impact of these processes on the development of age-related CV diseases, results from clinical trials targeting its components and the potential implementation of these advances into daily clinical practice
PCSK 9: A Link Between Inflammation and Atherosclerosis
No full textProprotein convertase subtilisin/Kexin 9 (PCSK 9) was revealed to be a key player in the lipid metabolism and therefore in the development and progression of atherosclerosis. PCSK 9 binds to the low-density lipoprotein (LDL) receptor, induces its degradation, and increases circulating blood LDL. As a result, PCSK 9 inhibitors represent an essential pillar in cardiovascular risk reduction therapies due to their highest good LDL decreasing properties. While the influence of PCSK 9 on lipid metabolism has been widely investigated, the full pathophysiological spectrum of PCSK 9 is yet to be determined. Statins have already been demonstrated to have beneficial anti-inflammatory effects. In this context, evidence suggests that PCSK 9 also interferes with inflammatory processes and thereby contributes to the development of atherosclerosis. As lipid metabolism on its own affects inflammatory processes, it is difficult to distinguish between lipid-dependent and -independent inflammatory properties of PCSK 9. A body of evidence has revealed that PCSK9 LDL-independently regulates the secretion of pro-inflammatory cytokines and inflammation-underlying pathways in vascular walls. In contrast, recent observations suggest that PCSK9 interacts with lectin-like oxidized LDL receptor-1 (LOX-1) and dampens inflammatory responses through LDL reduction. In conclusion, this review provides mounting evidence indicating how PCSK9 promotes vascular inflammation and subsequent atherosclerosis to shed light on the anti-inflammatory effects of PCSK9 inhibitors in preventing atherosclerosis
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