Obesity and the risk of heart failure

5 The activity of cyclin-dependent protein kinase p34cdc2 is regulated by phosphorylation. In this study, we show that the presence of phosphatase inhibitors can have major effects on the levels of phosphorylation and the activities of the kinase extracted from cells. The combination of okadaic acid and sodium vanadate was most effective in protecting p34cdc2 against cellular phosphatases. In the absence of these inhibitors, p34cdc2 was dephosphorylated with an altered activity, indicating that phosphatase activities remained high during extractions. In contrast to when both inhibitors were used, lower activity of the kinase was found when only sodium vanadate was used, whereas higher activity was found in the presence of okadaic acid. Other conventional phosphatase inhibitors such as NaP, NaRS03 and glycero12-phosphate, were not effective in preventing dephosphorylation from p34cdc2 in whole cell lysates.

The Cell Cycle

Autophagy contributes to the maintenance of intracellular homeostasis in most cells of cardiovascular origin, including cardiomyocytes, endothelial cells, and arterial smooth muscle cells Mitophagy is an autophagic response that specifically targets damaged, and hence potentially cytotoxic, mitochondria As these organelles occupy a critical position in the bioenergetics of the cardiovascular system, mitophagy is particularly important for cardiovascular homeostasis in health and disease Consistent with this notion, genetic defects in autophagy or mitophagy have been shown to exacerbate the propensity of laboratory animals to spontaneously develop cardiodegenerative disorders Moreover, pharmacological or genetic maneuvers that alter the autophagic or mitophagic flux have been shown to influence disease outcome in rodent models of several cardiovascular conditions, such as myocardial infarction, various types of cardiomyopathy, and atherosclerosis In this review, we discuss the intimate connection between autophagy, mitophagy, and cardiovascular disorders

Autophagy and Mitophagy in Cardiovascular Disease.

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR-S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.

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Interventions to Slow Aging in Humans: Are We Ready?

Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

/pdf/il-11-is-a-crucial-determinant-of-cardiovascular-fibrosis-4psms0zu9a.pdf

IL-11 is a crucial determinant of cardiovascular fibrosis

Murine models have been utilized with increasing frequency mainly due to availability of genetically engineered models With advancement in high spatial and temporal resolution, echocardiography is used extensively for the evaluation of cardiovascular function in murine models of cardiovascular disease This review summarizes the general applications and methods involved in echocardiography used to study mouse models for cardiovascular research, based on 20 years of experience in our laboratory The goal of this article is to provide a practical guide to the use of echo techniques in mice to evaluate cardiac systolic and diastolic function

/pdf/echocardiography-in-mice-3inf6jd8br.pdf

Echocardiography in Mice

The majority of current cardiovascular research involves studies in genetically engineered mouse models. The measurement of heart rate is central to understanding cardiovascular control under normal conditions, with altered autonomic tone, superimposed stress or disease states, both in wild type mice as well as those with altered genes. Electrocardiography (ECG) is the "gold standard" using either hard wire or telemetry transmission. In addition, heart rate is measured or monitored from the frequency of the arterial pressure pulse or cardiac contraction, or by pulse oximetry. For each of these techniques, discussions of materials and methods, as well as advantages and limitations are covered. However, only the direct ECG monitoring will determine not only the precise heart rates but also whether the cardiac rhythm is normal or not.

Heart Rate and Electrocardiography Monitoring in Mice

The use of mice for the evaluation and study of cardiovascular pathophysiology is growing rapidly, primarily due to the relative ease for developing genetically engineered mouse models. Arterial pressure monitoring is central to the evaluation of the phenotypic changes associated with cardiovascular pathology and interventions in these transgenic and knockout models. There are four major techniques for measuring arterial pressure in the mouse: tail cuff system, implanted fluid filled catheters, Millar catheters and implanted telemetry systems. Here we provide protocols for their use and discuss the advantages and limitations for each of these techniques .

/pdf/arterial-pressure-monitoring-in-mice-swm80utylb.pdf

Arterial Pressure Monitoring in Mice.

Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced β-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic β-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsα or β-adrenergic receptors in transgenic mice results in enhanced cardiac function in young animals, but with prolonged overstimulation of this pathway, cardiomyopathy develops in these mice as they age. Similarly, chronic sympathomimetic amine therapy increases morbidity and mortality in patients with heart failure. Conversely, the use of β-blockade has proven to be of benefit and is currently part of the standard of care for heart failure. It is conceivable that interrupting distal mechanisms in the β-adrenergic receptor-G protein-adenylyl cyclase pathway may also provide targets for future therapeutic modalities for heart failure. Interestingly, there are two major isoforms of adenylyl cyclase (AC) in the heart (type 5 and type 6), which may exert opposite effects on the heart, i.e., cardiac overexpression of AC6 appears to be protective, whereas disruption of type 5 AC prolongs longevity and protects against cardiac stress. The goal of this review is to summarize the paradigm shift in the treatment of heart failure over the past 50 years from administering sympathomimetic amine agonists to administering β-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC.

/pdf/modulation-of-b-adrenergic-receptor-signaling-in-heart-4qo0tczsi7.pdf

Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5

Calorie restriction (CR) is the most widely studied intervention protecting from the adverse effects of aging. Almost all prior studies have examined the effects of CR initiated in young animals. Studies examining the effects of CR on development of aging cardiomyopathy found only partial prevention. The major goal of this study was to determine whether CR initiated after aging cardiomyopathy developed could reverse the cardiomyopathy. Aging cardiomyopathy in 2-year-old mice was characterized by reduced left ventricular (LV) function, cardiac hypertrophy, and increased cardiac apoptosis and fibrosis. When short-term (2 months) CR was initiated after aging cardiomyopathy developed in 20-month-old mice, the decrease in cardiac function, and increases in LV weight, myocardial fibrosis and apoptosis were reversed, such that the aging hearts in these mice were indistinguishable from those of young mice or mice where CR was initiated in young mice. If apoptosis was the mechanism for protecting against aging cardiomyopathy, then total myocyte numbers should have reverted to normal with CR, but did not. However, the alterations in cytoskeletal proteins, which contribute to aging cardiomyopathy, were no longer observed with CR. This is the first study to demonstrate complete prevention of aging cardiomyopathy by CR and, more importantly, that instituting this intervention even later in life can rapidly correct aging cardiomyopathy, which could have important therapeutic implications.

/pdf/calorie-restriction-can-reverse-as-well-as-prevent-aging-2cn3f32e3i.pdf

David Ho

Papers

Echocardiography in Mice

Heart Rate and Electrocardiography Monitoring in Mice

Arterial Pressure Monitoring in Mice.

Modulation of β-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5

Calorie restriction can reverse, as well as prevent, aging cardiomyopathy