Wnt/β-catenin signaling is downregulated but restored by nutrition interventions in the aged heart in mice

Aging hallmarks include decreased progenitor cell functions. The Wnt/β-catenin signaling pathway has emerged as a key player in cellular aging in recent years. Wnt activity changes in aged tissues including skin, serum, muscle and artery. In heart, it is hypothesized that Wnt signaling increases with aging and this signaling drives cardiac progenitor cells into fibrogenic lineage. However, experimental evidence supporting this hypothesis has not been established. Here we take a bioinformatics data mining approach, utilizing pre-existing data, to study cardiac aging gene expression data in mice. Contrary to the hypothesis, our study shows that the Wnt/β-catenin signaling is down-regulated in aged heart in mice. Nutrition treatment, with calorie restriction and Resveratrol supplementation, known to retard aging, opposes heart aging by restoring Wnt/β-catenin signaling level in the old heart. In addition, the expression of β-catenin gene, a key regulator of the Wnt/β-catenin signaling pathway, decreases up to 3-fold in aged heart, but is restored to levels found in young heart with methods of nutrition intervention. Combined with database search, our study suggests that some of bioflavonoids may have potential therapeutic benefits to heart aging.     

Over-nutrition and metabolic cardiomyopathy

Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.     

Inflammatory Bowel Disease and Cardiovascular Diseases

BackgroundEmerging data showed patients with chronic inflammatory disorders, including inflammatory bowel disease, are more likely to develop atherosclerotic cardiovascular diseases, heart failure, and atrial fibrillation. This article aims to review the evidence of those associations.MethodsPubMed was searched from inception to January 2022 using the keywords, including inflammatory bowel diseases, Crohn disease, ulcerative colitis, atherosclerotic cardiovascular disease, coronary artery disease, cardiovascular disease, atrial fibrillation, heart failure, and premature coronary artery disease. Relevant literature, including retrospective/prospective cohort studies, clinical trials, meta-analyses, and guidelines, were reviewed and summarized.ResultsBoth ulcerative colitis and Crohn disease are associated with an increased risk of atherosclerotic cardiovascular diseases, cerebrovascular accidents, premature coronary artery disease, and atrial fibrillation. Ulcerative colitis is associated with an increased risk of heart failure. The increased atrial fibrillation occurred during inflammatory bowel disease flares and persistent activity but not during periods of remission. Hypotheses for the mechanism underlying the association of inflammatory bowel disease and atherosclerotic cardiovascular diseases include shared risk factors (ie, obesity, diabetes, smoking, diet) and pathophysiology (gut microbiome dysfunction) or adverse effects from inflammatory bowel disease itself or its treatment (ie, chronic inflammation, dyslipidemia, thrombocytosis, steroids).ConclusionInflammatory bowel disease is associated with an increased risk of atherosclerotic cardiovascular diseases, heart failure, and atrial fibrillation. A multidisciplinary team with gastroenterologists and cardiologists is needed to optimize the care for patients with inflammatory bowel disease and associated cardiac diseases.     

Growth factors, nutrient signaling, and cardiovascular aging

Growth factors regulated by specific macronutrients have been shown to promote aging and accelerate mortality in the majority of the organisms studied. In particular, the enzymes activated by growth hormone, insulin, and insulin-like growth factor-1 in mammals and their orthologs in simple model organisms represent perhaps the best-understood proteins involved in the aging process. Dietary restriction, which reduces the level of insulin-like growth factor-1 and of other growth factors, has been associated with protection from diabetes, cancer, and cardiovascular diseases, and deficiencies in growth hormone signaling and insulin-like growth factor-1 are strongly associated with protection from cancer and diabetes in both mice and humans; however, their role in cardiac function and cardiovascular diseases is controversial. Here, we review the link between growth factors, cardiac function, and heart disease with focus on the cardioprotective and sensitizing effect of growth factors in both model organisms and humans.     

Notch Signaling in Cardiovascular Disease and Calcification

Recent increase in human lifespan has shifted the spectrum of aging-related disorders to an unprecedented upsurge in cardiovascular diseases, especially calcific aortic valve stenosis, which has an 80% risk of progression to heart failure and death. A current therapeutic option for calcified valves is surgical replacement, which provides only temporary relief. Recent progress in cardiovascular research has suggested that arterial and valve calcification are the result of an active process of osteogenic differentiation, induced by a pro-atherogenic inflammatory response. At molecular level, the calcification process is regulated by a network of signaling pathways, including Notch, Wnt and TGFbeta/BMP pathways, which control the master regulator of osteogenesis Cbfa1/Runx2. Genetic and in vitro studies have implicated Notch signaling in the regulation of macrophage activation and cardiovascular calcification. Individuals with inactivating Notch1 mutations have a high rate of cardiovascular disorders, including valve stenosis and calcification. This article reviews recent progress in the mechanism of cardiovascular calcification and discusses potential molecular mechanisms involved, focusing on Notch receptors. We propose a calcification model where extreme increases in vascular wall cell density due to inflammation-induced cell proliferation can trigger an osteogenic differentiation program mediated by Notch receptors. Key Words: Calcification, cardiac valve, inflammation, Notch signaling, mesenchymal stem cells, atherosclerosis.     

Klotho与心血管疾病的关系及其生物学机制

Klotho是重要的内源性多效蛋白,参与衰老和钙磷代谢等病理生理过程,与心血管疾病密切相关。近期的临床研究发现低水平的Klotho与更多的心血管危险因素关联,并能预测心血管疾病的发病风险和不良预后;基础研究也表明Klotho在维持血管稳态和正常心功能中发挥了至关重要的作用。Klotho可以促进一氧化氮(NO)的生成,抑制炎症因子和黏附分子的表达,介导抗氧化、抗凋亡、抗衰老的生物学效应,延缓动脉粥样硬化及血管钙化,并抑制心肌肥厚和纤维化。Klotho或可作为一个新的干预靶点,为心血管疾病的防治提供新的思路。文章就Klotho与心血管疾病的关系及其潜在的生物学机制做一综述。     

Aging and endothelial dysfunction

Aging is the major risk factor for the development of cardiovascular diseases, the leading cause of morbidity, mortality and disability in western countries. Mounting data suggest that cardiovascular structure and function change with time as result of an "aging process", regarded as an independent process which accompanies aging, interwines and modulates superimposed traditional cardiovascular risk factors to determine the peculiar occurrence, presentations and prognosis of heart disease in the elderly. A whole body of data underlies the impairment of endothelial function due to oxidative stress as a crucial feature of the aging process acting on the cardiovascular system. Insights into molecular and cellular mechanisms of age-associated endothelial dysfunction may provide new strategies to treat age-related cardiovascular diseases.     

Research Agenda for Cardiovascular Aging: Humans to Molecules

Clinical manifestations of specific cardiovascular diseases, e.g., atherosclerosis and hypertension, that lead to heart failure and stroke likely become altered in older persons of advanced age because interactions occur between age-associated cardiovascular changes in health and specific pathophysiologic mechanisms that underlie cardiovascular diseases. The interactions result in a lower threshold for clinical symptoms, and greater severity and poorer prognosis of these diseases in older vs. younger persons. In this regard, cardiovascular changes that occur during aging in health ought not to be considered to reflect a "normal process"; rather these specific age-associated changes must be construed as specific "risk factors" for the aforementioned cardiovascular diseases and ought to become targets of interventions designed to prevent the epidemic of cardiovascular disease in later life. Such a strategy would thus advocate preventive treatment for what is now considered to be "normal cardiovascular aging." Effective and efficient prevention of the "risks" associated with cardiovascular aging in apparent health requires a fundamental understanding of these changes ranging in scope from humans to molecules. An opinion regarding specific directions for research aimed toward the achievement of this understanding is provided.     

Views from within and beyond: narratives of cardiac contractile dysfunction under senescence

Senescence is associated with enhanced risk of cardiovascular diseases. It is generally considered that decline in growth hormones (such as insulin-like growth factor I), intrinsic myocardial and endothelial functions, as well as accumuation of reactive oxygen species with increased age may contribute to cardiovascular senescence. It is believed that heart function, especially cardiac reserve declines with advanced age. However, most experimental and clinical investigations on ventricluar function only included young or adult subjects and failed to address this important age issue in heart pathophysiology. Although senescent but otherwise healthy hearts may possess normal pumping function at the resting or non-stressed state, some aging-associated factors such as accumulation of reactive oxygen species and activation of selective stress signaling pathways may interact with certain risk factors and compromise overall cardiac function. The precise cause and progression of compromised cardiac function in the elderly remain controversial. This review will focus on senescene-related alterations in cardiac contractile function with a special emphasis on oxidative stress and activation of stress signaling.     

Study of cardiovascular risk factors and hemostatic molecular markers in elderly persons

In this study, plasma concentrations of hemostatic molecular markers were investigated in 118 elderly persons with normal renal function (aged 65 to 97 years) who could manage their activities of daily living (ADL) by themselves, to find a strategy for conservation or elevation of ADL and quality of life (QOL). In all subjects, the frequency by which hemostatic markers exceeded their upper limit of normal range was 35.9% for thrombin-antithrombin HI complex (> or = 3.7 ng/ml), 38.3% for soluble fibrin monomer (> or = 4.0 microg/ml), 41.8% for D-dimer (> or = 1.0 microg/ml), 49.0% for plasmin-alpha2 plasmin inhibitor complex (> or = 1.0 microg/ml), and 53.7% for thrombomodulin (> or = 20 ng/ml). The mean plasma levels of these markers were slightly higher than the upper limit of their normal range. These markers were also investigated in samples of patients with and without cardiovascular risk factors and with and without cardiovascular diseases (ischemic heart disease and/or cerebral infarction). Furthermore, the results were analyzed in relationships between cardiovascular disease and cardiovascular risk factor or aging. The findings suggest that aging exerts a stronger influence on plasma levels of these hemostatic molecular markers than the presence of cardiovascular risk factors and cardiovascular diseases. From the viewpoint for conservation or elevation of ADL and QOL in elderly persons, also other factor, such as drug intake, lifestyle, aging, and so on, must be considered to clarify the relationship between the plasma levels of the hemostatic molecular markers and cardiovascular risk factors or cardiovascular diseases.     

Arterial aging: is it an immutable cardiovascular risk factor?

Age is the dominant risk factor for cardiovascular diseases. However, until recently, convincing mechanistic or molecular explanations for the increased cardiovascular risks conferred by aging have been elusive. Aging is associated with alterations in a number of structural and functional properties of large arteries, including diameter, wall thickness, wall stiffness, and endothelial function. Emerging evidence indicates that these age-associated changes are also accelerated in the presence of cardiovascular diseases, and that these changes are themselves risk factors for the appearance or progression of these diseases. In this review, the evidence demonstrating that arterial aging is accelerated in cardiovascular diseases and that accelerated arterial aging is a risk factor for adverse cardiovascular outcomes is briefly reviewed, and selected advances in vascular biology that provide insights into the mechanisms that may underlie the increased risks conferred by arterial aging are summarized. Remarkably, a host of biochemical, enzymatic, and cellular alterations that are operative in accelerated arterial aging have also been implicated in the pathogenesis and progression of arterial diseases. These vascular alterations are thus putative candidates that could be targeted by interventions aimed at attenuating arterial aging, similar to the lifestyle and pharmacological interventions that have already been proven effective. Therefore, the notion that aging is a chronological process and that its risky components cannot be modulated is no longer tenable. It is our hope that a greater appreciation of the links between arterial aging and cardiovascular diseases will stimulate further investigation into strategies aimed at preventing or retarding arterial aging.     

Ageing and the cardiovascular system

Heart disease is the most common cause of death in elderly people. Cardiovascular aging is a continuous and irreversible process. It has a decline rate that varies among individuals and can be modulated by three conceptually different influences, namely, physiological changes due to the passage of time, adaptive sequeles of previous diseases or surgery in younger life, and influence of the individual lifestyle or their own cardiovascular risk factors. The main practical consequences of aging processes are a progressive change in the morphological, functional, and semiological characteristics of the cardiovascular system and an increase in the number of age-related cardiovascular disorders.     

老年眩晕合并心脑血管病及其临床用药研究现状

当前我国已经进入老龄化社会,老年眩晕合并心脑血管病发生率逐年递增,合并疾病的数量和复杂性也随着年龄的增长而增加。本文将重点介绍老年眩晕的发病率、病因、病理生理机制及危险因素,阐述老年眩晕与心脑血管病的关系及相互作用机制。近年来发现老年眩晕与高血压、脑卒中、冠心病、心房颤动等多种心脑血管病相关。现就老年眩晕合并心脑血管病的最新研究进展及其临床用药研究现状进行综述。     

Pregnancy and the cardiovascular system

The cardiovascular system undergoes important adaptations during pregnancy to accommodate for fetal requirements. This causes a hemodynamic burden on patients with underlying heart disease, and is associated with significant morbidity and mortality. Moreover, certain cardiovascular diseases may be due to pregnancy. Although unusual, these diseases can pose a threat to the pregnant woman and her fetus. This review will discuss cardiovascular adaptations to pregnancy as well as the risk of pregnancy in patients with underlying heart disease. It will also provide a brief overview of cardiovascular disorders associated with pregnancy.     

Control of aging and longevity by IGF-I signaling

Animal models have established the IGF-I signaling pathway as a key modulator of aging in rodents and invertebrates. Considerable evidence suggests that reduced exposure of tissue to IGF-I is associated with an extended lifespan in these species. In humans, IGF-I is linked to various age-related diseases that are limiting factors for youthful longevity. On one hand, reduced IGF-I activity is associated with significant morbidity in adulthood with an increased risk of developing cardiovascular disease, diabetes, osteoporosis and neurodegenerative diseases. On the other hand, elevated IGF-I levels have been linked to cancer risk given the role of IGF in mediating normal and malignant tissue growth. Thus, IGF is clearly involved in modulating disease of aging; however, the mechanism appears to be complex and interdependent on additional modulating factors. It is attractive to hypothesize that maximal human survival depends on tight regulation of the GH-IGF axis and maintenance of optimal IGF-I action in order to prevent morbidities associated with either deficient or excessive state. Specifically, it is possible that lower levels of IGF-I during early adulthood followed by higher levels of IGF-I later in life may be most beneficial for human longevity by addressing age-specific morbidities.     

Redox balance in the aged endothelium

The endothelium is located in a strategic anatomical position within the blood vessel wall and thus constitutes a barrier between the blood and all tissues. The integrity of the endothelial cells, which line the entire circulatory system like wallpaper, is essential to prevent the onset of cardiovascular disorders. Aging is one of the major risk factors for the development of heart and vascular diseases. However, over the past years it has become clear that the functional capacity of endothelial cells declines with age and that physiological aging occurs independently of pathological changes. One important mechanism contributing to the onset of the aging process is the disturbance of the cellular redox homeostasis. Two key molecules involved in maintaining the delicate balance between oxidative and antioxidative systems are NADPH oxidase 4, an enzyme whose sole function is to produce reactive oxygen species and the oxidoreductase thioredoxin-1, which reduces oxidized proteins. Therefore, this review will focus on the role of these two proteins in cardiovascular aging.     

Statins and hypertension

Hypertension and dyslipidemia are frequently associated as risk factors for cardiovascular diseases. Statins are among the most potent drugs to correct hypercholesterolemia, and their use across a wide range of cardiovascular risk levels significantly reduced morbidity and mortality in large intervention trials. Aside from (or in addition to) reducing plasma cholesterol, statins also reduce blood pressure, another effect associated with cardiovascular risk reduction by other antihypertensive drugs. This review examines the proposition that a part of the statins' beneficial effect in cardiovascular diseases may result from direct effects on blood pressure regulation, perhaps independent of lipid lowering. Potential molecular mechanisms are considered (e.g., "pleiotropic" effects on endothelial vasoactive mediators, oxidant stress, or inflammation), all of which may affect the central or peripheral control of blood pressure homeostasis, as well as modulate target organ damage. In particular, potential effects of statins on blood pressure and heart rate variability open new perspectives for a better tailoring of drug treatment in high-cardiovascular risk patients.     

Risk factors for pneumonia in patients with cardiovascular diseases

A case-control-study was performed to identify patients at particularly high risk of community-acquired pneumonia and nosocomial pneumonia with a special focus on cardiovascular diseases as potential risk factors. Thirty-six consecutive hospitalized patients with cardiovascular diseases and pneumonia were matched with 36 controls also suffering from cardiovascular diseases but without pneumonia. From all cardiovascular diseases only heart failure proved to be an independent risk factor for pneumonia (OR 5.69, 95 % KI 1.69 - 19.04, p = 0.0048). Both chronic (p = 0.009) and acute heart failure (p = 0.028) were associated with an increased risk of pneumonia. The risk of pneumonia was closely related to the degree of ventricular function impairment. Coronary heart disease, valvular disease, arrythmia, myocarditis, endocarditis and cardiomyopathy did not increase the risk for pneumonia unless accompanied by heart failure. Pulmonary (OR 9.24, 95 % KI 1.48 - 57.74, p = 0.00174) and renal diseases (OR 7.49, 95 % KI 1.38 - 40.76, p = 0.0197) were validated as additional independent risk factors. A history of smoking was also associated with an increased risk of pneumonia (p = 0,023). This study supports the hypothesis that heart failure resulting from cardiovascular disease and not cardiovascular disease itself mounts the risk for pneumonia.     

非编码RNA对心血管衰老调节的作用及进展

衰老是心血管疾病的重要危险因素之一。随着世界老龄化进程加快,心血管衰老性疾病患者的发病率和死亡率也显著增加。非编码RNA为探索心血管衰老性疾病提供了新的分子视角,众多研究表明非编码RNA在心血管衰老过程中发挥重要作用。本文综述了非编码RNA对心血管衰老调节的作用及进展,以期为心血管衰老性疾病提供新的治疗策略。