Association between sphingolipids and cardiopulmonary fitness in. Perfusion of hearts with triglyceriderich particles. Obesityrelated heart disease is characterized by a signature set of cardiac defects generally referred to as lipotoxic cardiomyopathy lcm. Lipotoxicity likely contributes to cardiac dysfunction in i obesityrelated and ii diabetic cardiomyopathy, and pathological assessments reveal lipid accumulation in these specimens. Endothelial nogob regulates sphingolipid biosynthesis to. Two human conditions are thought to be caused by excess cardiac lipid accumulation. The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemiarelated heart failure. Sphingolipids are a major class of lipids, comprising various species with diverse functions. Cardiac intracellular lipid accumulation steatosis is a pathophysiological phenomenon observed in starvation and diabetes mellitus. The cardiovascular disease cvd frequently developed during metabolic syndrome and type2 diabetes mellitus is associated with increased levels of aggregationprone small ldl particles. They are mostly in membranes, but are also major constituents of lipoproteins.
Lipotoxic cardiomyopathy is caused by excessive lipid accumulation in myocardial cells and it is a form of cardiac dysfunction. They serve as biologically active components of cell membrane and are involved. Phospholipid homeostasis regulates lipid metabolism and. Many investigations suggest the pivotal role of sphingolipids in the pathogenesis of lifestyle diseases such as myocardial infarction, hypertension, stroke, diabetes mellitus type 2 and obesity. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Goldberg, mdb, introduction obesity is associated with an elevated risk of chronic diseases, including diabetes and cardiovasculardisease.
Heart sphingolipids in health and disease request pdf. In lipid storage disorders such as niemannpick and sandhoff diseases and gm1 gangliosidosis, metabolic cardiomyopathy was also diagnosed 24. Ceramides lipotoxic inducers of metabolic disorders. In the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure. Lipotoxic cardiomyopathy lcm is characterized by abnormal myocardial accumulation of lipids, including ceramide. Obesity may result in heart failure by inducing hemodynamic and myocardial changes that lead to cardiac dysfunction, or due to an increased predisposition to other heart failure risk factors. Adenoviral gene transfer of sphingosine kinase 1 protects. In rodent models of dbcm, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid sfa oversupply and. Heart sphingolipids in health and disease springerlink. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because of their enigmatic nature. The functions of sphingolipids are still being discovered, but there are at least three, i. The observation of lipids, especially lipidomics profiling, can provide an insight into the know.
Tg mice demonstrate increased expression of genes involved in glucose and fatty acid metabolism with no evidence of lipid accumulation or cardiac dysfunction. Sphingolipids are important structural and signaling molecules. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure heart failure clinics, vol. In some models, the capacity for triglyceride accumulation is associated with less myocardial damage and improved cardiac function.
Sphingolipids in cardiovascular diseases and metabolic. Monkey model for hypertrophic cardiomyopathy identified at. Aggregated ldl aggldl internalization is mediated by lowdensity lipoprotein receptorrelated protein1 lrp1 promoting intracellular cholesteryl ester ce accumulation. Heart failure hf is a leading cause of morbidity and mortality in the united states, and its prevalence continues to rise despite the overall decline in cardiovascular disease cvd related morbidity and mortality. The plasma levels of s1p significantly decreased, but the plasma levels of cer significantly increased at 1 and 6 h after myocardial infarction, but both sphingolipids returned to the control values after 24 h from the cardiac incident. They identified several ceramideinteracting proteins, whose subsequent cardiacspecific manipulation can prevent lcm by altering caspase activation. Ceramideprotein interactions modulate ceramideassociated. Diabetic cardiomyopathy dcm is a serious cardiac dysfunction induced by changes in the structure and contractility of the myocardium that are initiated in part by alterations in energy substrates. In obesity and dyslipidemia, the oversupply of fat to tissues not suited for lipid storage induces cellular dysfunction that underlies diabetes and cardiovascular disease i. Several animal models of myocardial lipotoxicity have. Clinical studies have clearly shown a correlation between the accumulation of triglycerides and heart dysfunction. Sphingolipids are found in essentially all animals, plants, and fungi, as well as some prokaryotic organisms and viruses. Accumulationoflipotoxicmetabolites in nonadipocyte tissues may be a major cause of dilated cardiomyopathy in patients.
However, fatty acid oxidation yields lower atp production. Myocardial sphingoid base synthesis utilizes myristate. In animal models, the ceramide accumulation within the myocardium is responsible for a direct toxic effect on myocardial fibrils, cardiomyocytes apoptosis, and altered cardiac. Sphingomyelin, sphingolipids, cardiovascular implications. Endurance exercise resistance to lipotoxic cardiomyopathy. Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. Machine learning reveals serum sphingolipids as cholesterol. Reader jr, canfield dr, lane jf, kanthaswamy s, ardeshir a. The underlying mechanisms of dcm are still under controversial. For example, overexpression of diacylglycerol acyl transferase 1 dgat1 promotes triglyceride accumulation, decreases ceramide accumulation and preserves cardiac function in the acsl1 lipotoxic cardiomyopathy. Alteration of energy substrates and ros production in.
These observations strongly support the therapeutic potential of pharmaceuticals targeting sphingolipids, as well as diagnostic tests using the c16c24 ceramide ratio as a marker of risk. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac. Elevated ceramide correlates with lipotoxic cardiomyopathy the accumulation of neutral lipids in or around the myocardium is observed in humans or animal models with nonischemic heart failure,1,2,22,23 and it is hypothesized that excess lipid contributes. Despite excess of plasma glucose and lipids, the diabetic heart almost exclusively depends on fatty acid degradation. Definition of diabetic or lipotoxic cardiomyopathy.
The molecular means by which these particular ceramides drive tissue dysfunction has received considerable attention 10. Hf in obesity may be due to an increased predisposition to other hf risk factors such as coronary artery disease cad, diabetes mellitus, hypertension, dyslipidemia, insulin resistance ir, metabolic syndrome, kidney disease, obstructive sleep apnea osa, and cardiac conduction abnormalities, or occur solely as a. Sphingomyelin, ceramide, exercise, cardiovascular disease. However, whether ceramide is relevant to cardiac failure in humans is unclear.
Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure. This leads to deterioration of cardiac contractility and disruptions in the cardiac conduction system, which may culminate in heart failure and arrhythmias, respectively. Diabetic cardiomyopathy dbcm, which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. Moreover experimental manipulations that promote cardiacspecific lipid accumulation in mice induce cardiac dysfunction. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure taesik park, phda, ira j. Cardiomyopathy in obesity, insulin resistance and diabetes. Classic hallmarks of lcm recapitulated in animal models include left ventricular hypertrophy, diastolic with or without systolic dysfunction, contractile defects, and cardiac steatosis goldberg et al. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure ncbi. Cnprc pathologists published the analysis of 20 years of findings on sudden cardiac death in the cnprc rhesus monkeys in the prominent journal comparative medicine april 4, 2016. Some studies suggest that sphingolipids are important factors in cellular signal transduction. Ceramide was found to be involved in the pathogenesis of cardiac dysfunction in animal models of ischemiareperfusion injury, type 2 diabetes and lipotoxic cardiomyopathy. Left ventricular hypertrophy in rhesus macaques macaca mulatta at the california national primate research center 1992 2014. Lipids, as key players in cellular heat stress management short presentations from abstracts.
This might be a reaction to vessel wall injury that accompanies infections, immune disease, and perhaps diabetes and renal failure. Myristate is a novel potential substrate for sphingoid base synthesis. Jci insight endothelial nogob regulates sphingolipid. Hearts with overexpression of anchored lipoprotein lipase lpl by cardiomyocytes hlpl gpi mice develop a lipotoxic cardiomyopathy. Cells free fulltext lrp1mediated aggldl endocytosis. Perilipin 2 plin2 is a lipid droplet ldassociated protein. Circulating ceramides are inversely associated with. Cardiomyopathy in patients with obesity, insulin resistance, or diabetes in the absence of other comorbidities, including hypertension, coronary artery disease and valvular heart disease, is defined as diabetic cardiomyopathy or lipotoxic cardiomyopathy. Although several key molecular pathways regulating cardiac hypertrophy have been defined 1, 2, not all hypertrophy is detrimental, and a. In this process, it is likely that there are also changes in the contents of sphingolipids. Cardiac hypertrophy induced by pressure overload is associated with pathological myocardial and vascular changes that can lead to cardiac dysfunction and, ultimately, heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of. Direct cardiac lipotoxicity has been described where lipid accumulation in the heart results in cardiac dysfunction inexplicable of other heart failure risk factors.
Association between sphingolipids and cardiopulmonary. Manifestations and mechanisms of myocardial lipotoxicity. Pdf the long term benefits conferred by cardiac rehabilitation cr in those with cad are strongly linked with an improvement in cardiopulmonary. Phospholipid homeostasis regulates lipid metabolism and cardiac function through srebp signaling in drosophila huiying lim,1 weidong wang,2 robert j. Sphingolipids and their metabolism in physiology and. Cardiac overexpression of perilipin 2 induces dynamic. Alteration of sphingolipid biology has recently been correlated with various forms of cardiovascular disease, including atherosclerotic heart disease, cardiomyopathy, heart failure, and hypertension 43 46, suggesting a potential role for sphingolipids in. In recent years, the role of sphingolipids in physiology and pathophysiology of the heart attracted much attention. Glycolytic enzymes and transporters are impaired by fatty acid metabolism, leading to accumulation of glucose derivatives. Request pdf sphingolipids, lipotoxic cardiomyopathy, and cardiac failure in the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids may be a cause of heart failure.
These compounds play important roles in signal transduction and cell recognition. Preservation of acyl coenzyme a attenuates pathological. Plasma ceramides and sphingomyelins in relation to heart. The accumulation of neutral lipids in or around the myocardium is observed in humans or animal models with nonischemic heart failure, 1,2,22,23 and it is hypothesized that excess lipid contributes to the development of cardiac dysfunction. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including. Jci ceramide synthase 5 mediates lipidinduced autophagy. Animal experiments suggest that ceramide is implicated in pathogenesis of cardiac dysfunction associated with obesity and diabetes. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. However, a recent study in mice showed that inhibition of acid sms does not result in improved heart function or survival after an induced mi despite reducing ischaemiainduced ceramide accumulation. In addition to being structural elements of membranes, many sphingolipids are bioactive and regulate a. Changes of myocardial lipidomics profiling in a rat model. Of the myriad lipids that accrue under these conditions, sphingolipids such as ceramide or its metabolites are amongst the most deleterious because they disrupt insulin sensitivity. Diabetic cardiomyopathy is a syndrome in which heart failure is not caused by ischemic heart disease or hypertension.
While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and. Coronary artery disease cad is the most common type of cardiovascular. The role of sphingolipids in the cardiovascular system sphingolipids are components of the cardiomyocytes. To characterize cardiac fatty acid fa and triglyceride tg metabolism in these mice and to determine whether changes in lipid metabolism precede cardiac dysfunction, hearts from young mice were perfused in langendorff mode with 14. For example, in a lipotoxic cardiomyopathic mouse model with cardiacspecific overexpression of glycosylphosphatidylinositolanchored human lipoprotein lipase, it was observed that ceramide levels increased by 45% compared to control mice. Association between sphingolipids and cardiopulmonary fitness in coronary artery disease patients undertaking cardiac rehabilitation.
It is noteworthy that jiang and colleagues found that plasma levels of sphingolipids are an independent risk factor for coronary heart disease jiang et al. Request pdf sphingolipids, lipotoxic cardiomyopathy, and cardiac failure in the setting of obesity and type 2 diabetes mellitus, the ectopic disposition of lipids. Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. Sphingolipids, lipotoxic cardiomyopathy and cardiac failure pablo v. Pdf sphingolipids in cardiovascular diseases and metabolic.
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