Calorie restriction and resveratrol in cardiovascular health and disease

AbstractCalorie restriction is one of the most effective nutritional interventions that reproducibly protects against obesity, diabetes and cardiovascular disease. Recent evidence suggests that even when implemented over a short period, calorie restriction is a safe and effective treatment for cardiovascular disease. Herein, we review the effects of calorie restriction on the cardiovascular system as well as the biological effects of resveratrol, the most widely studied molecule that appears to mimic calorie restriction. An overview of microarray data reveals that the myocardial transcriptional effects of calorie restriction overlap with the transcriptional responses to resveratrol treatment. In addition, calorie restriction and resveratrol modulate similar pathways to improve mitochondrial function, reduce oxidative stress and increase nitric oxide production that are involved in atherosclerosis prevention, blood pressure reduction, attenuation of left-ventricular hypertrophy, resistance to myocardial ischemic injury and heart failure prevention. We also review the data that suggest that the effects of calorie restriction and resveratrol on the cardiovascular system may involve signaling through the silent information regulator of transcription (SIRT), Akt and the AMP-activated protein kinase (AMPK) pathways. While accumulating data demonstrate the health benefits of calorie restriction and resveratrol in experimental animal models, whether these interventions translate to patients with cardiovascular disease remains to be determined

Expression of monolysocardiolipin acyltransferase activity is regulated in concert with the level of cardiolipin and cardiolipin biosynthesis in the mammalian heart

BACKGROUND: Monolysocardiolipin acyltransferase (MLCL AT) catalyzes the acylation of monolysocardiolipin to cardiolipin in mammalian tissues. We previously reported that cardiac cardiolipin levels, MLCL AT and cardiolipin synthase activities were all elevated in rats made hyperthyroid by thyroxine treatment. In this study, we examined if cardiac mitochondrial MLCL AT activity was dependent upon the biosynthesis and level of cardiolipin in the heart. Rat heart mitochondrial MLCL AT activity was determined under conditions in which the levels of cardiac cardiolipin and cardiolipin synthase activity were either reduced or unaltered using four different disease models in the rat. In addition, these parameters were examined in a murine model of cardiac cell differentiation. RESULTS: In rats made hypothyroid by treatment with 6-n-propyl-2-thiouracil in the drinking water for 34 days, cardiac cardiolipin content was decreased 29% (p < 0.025) and this was associated with a 32% decrease (p < 0.025) in cardiolipin synthase and a 35% reduction (p < 0.025) in MLCL AT activities. Streptozotocin-induced diabetes or hyperinsulinemia in rats did not affect cardiac cardiolipin content nor MLCL AT and cardiolipin synthase activities. Finally, cardiolipin content, MLCL AT and cardiolipin synthase activities were unaltered during murine P19 teratocarcinoma cell differentiation into cardiac myocytes. In all models, phospholipase A(2) activities were unaltered compared with controls. CONCLUSION: We propose a general model in which the expression of MLCL AT activity is regulated in concert with the biosynthesis and level of cardiolipin in the heart

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development

Maternal β-Cell Adaptations in Pregnancy and Placental Signalling: Implications for Gestational Diabetes

Rates of gestational diabetes mellitus (GDM) are on the rise worldwide, and the number of pregnancies impacted by GDM and resulting complications are also increasing. Pregnancy is a period of unique metabolic plasticity, during which mild insulin resistance is a physiological adaptation to prioritize fetal growth. To compensate for this, the pancreatic &beta;-cell utilizes a variety of adaptive mechanisms, including increasing mass, number and insulin-secretory capacity to maintain glucose homeostasis. When insufficient insulin production does not overcome insulin resistance, hyperglycemia can occur. Changes in the maternal system that occur in GDM such as lipotoxicity, inflammation and oxidative stress, as well as impairments in adipokine and placental signalling, are associated with impaired &beta;-cell adaptation. Understanding these pathways, as well as mechanisms of &beta;-cell dysfunction in pregnancy, can identify novel therapeutic targets beyond diet and lifestyle interventions, insulin and antihyperglycemic agents currently used for treating GDM

Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease

Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring

The Role of Adiponectin during Pregnancy and Gestational Diabetes

Pregnancy involves a range of metabolic adaptations to supply adequate energy for fetal growth and development. Gestational diabetes (GDM) is defined as hyperglycemia with first onset during pregnancy. GDM is a recognized risk factor for both pregnancy complications and long-term maternal and offspring risk of cardiometabolic disease development. While pregnancy changes maternal metabolism, GDM can be viewed as a maladaptation by maternal systems to pregnancy, which may include mechanisms such as insufficient insulin secretion, dysregulated hepatic glucose output, mitochondrial dysfunction and lipotoxicity. Adiponectin is an adipose-tissue-derived adipokine that circulates in the body and regulates a diverse range of physiologic mechanisms including energy metabolism and insulin sensitivity. In pregnant women, circulating adiponectin levels decrease correspondingly with insulin sensitivity, and adiponectin levels are low in GDM. In this review, we summarize the current state of knowledge about metabolic adaptations to pregnancy and the role of adiponectin in these processes, with a focus on GDM. Recent studies from rodent model systems have clarified that adiponectin deficiency during pregnancy contributes to GDM development. The upregulation of adiponectin alleviates hyperglycemia in pregnant mice, although much remains to be understood for adiponectin to be utilized clinically for GDM

The Role of Adiponectin during Pregnancy and Gestational Diabetes

Pregnancy involves a range of metabolic adaptations to supply adequate energy for fetal growth and development. Gestational diabetes (GDM) is defined as hyperglycemia with first onset during pregnancy. GDM is a recognized risk factor for both pregnancy complications and long-term maternal and offspring risk of cardiometabolic disease development. While pregnancy changes maternal metabolism, GDM can be viewed as a maladaptation by maternal systems to pregnancy, which may include mechanisms such as insufficient insulin secretion, dysregulated hepatic glucose output, mitochondrial dysfunction and lipotoxicity. Adiponectin is an adipose-tissue-derived adipokine that circulates in the body and regulates a diverse range of physiologic mechanisms including energy metabolism and insulin sensitivity. In pregnant women, circulating adiponectin levels decrease correspondingly with insulin sensitivity, and adiponectin levels are low in GDM. In this review, we summarize the current state of knowledge about metabolic adaptations to pregnancy and the role of adiponectin in these processes, with a focus on GDM. Recent studies from rodent model systems have clarified that adiponectin deficiency during pregnancy contributes to GDM development. The upregulation of adiponectin alleviates hyperglycemia in pregnant mice, although much remains to be understood for adiponectin to be utilized clinically for GDM

Extracellular Vesicles as an Index for Endothelial Injury and Cardiac Dysfunction in a Rodent Model of GDM

Gestational diabetes mellitus (GDM) increases risk of adverse pregnancy outcomes and maternal cardiovascular complications. It is widely believed that maternal endothelial dysfunction is a critical determinant of these risks, however, connections to maternal cardiac dysfunction and mechanisms of pathogenesis are unclear. Circulating extracellular vesicles (EVs) are emerging biomarkers that may provide insights into the pathogenesis of GDM. We examined the impact of GDM on maternal cardiac and vascular health in a rat model of diet-induced obesity-associated GDM. We observed a >3-fold increase in circulating levels of endothelial EVs (p p p p < 0.05). In summary, we observed maternal vascular and cardiac dysfunction in rodent GDM accompanied by increased circulating endothelial EVs and EV-associated mitochondrial DNA. Our study highlights a novel method for assessment of vascular injury in GDM and highlights vascular mitochondrial injury as a possible therapeutic target

Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat-high sucrose-feeding

Sarco(endo)plasmic reticulum calcium (CaThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author