The Cytoprotective Effects of Tumor Necrosis Factor Are Conveyed Through Tumor Necrosis Factor Receptor–Associated Factor 2 in the Heart

Fatty acid synthase (FAS) promotes energy storage through de novo lipogenesis and participates in signaling by the nuclear receptor PPAR␣ in noncardiac tissues. To determine if de novo lipogenesis is relevant to cardiac physiology, we generated and characterized FAS knockout in the myocardium (FASKard) mice. FASKard mice develop normally, manifest normal resting heart function, and have normal cardiac PPAR␣ signaling as well as fatty acid oxidation. However, they decompensate with stress. Most die within 1 h of transverse aortic constriction, probably due to arrhythmia. Voltage clamp measurements of FASKard cardiomyocytes show hyperactivation of L-type calcium channel current that could not be reversed with palmitate supplementation. Of the classic regulators of this current, Ca 2؉ / calmodulin-dependent protein kinase II (CaMKII) but not protein kinase A signaling is activated in FASKard hearts, and knockdown of FAS in cultured cells activates CaMKII. In addition to being intolerant of the stress of acute pressure, FASKard hearts were also intolerant of the stress of aging, reflected as persistent CaMKII hyperactivation, progression to dilatation, and premature death by ϳ1 year of age. CaMKII signaling appears to be pathogenic in FASKard hearts because inhibition of its signaling in vivo rescues mice from early mortality after transverse aortic constriction. FAS was also increased in two mechanistically distinct mouse models of heart failure and in the hearts of humans with end stage cardiomyopathy. These data implicate a novel relationship between FAS and calcium signaling in the heart and suggest that FAS induction in stressed myocardium represents a compensatory response to protect cardiomyocytes from pathological calcium flux.Storing energy preserves the function of many mammalian tissues during physiological and pathological stress. One of the ways that tissues store energy is through de novo lipogenesis, the synthesis of saturated fatty acids from carbohydrate precursors (1). This process, accomplished by iterative two-carbon additions to a fatty acid chain, is mediated by the multifunctional enzyme FAS 2 (2, 3). Initially relegated to cellular housekeeping, FAS was recently also shown to participate in intracellular signaling. Whole body FAS-deficient embryos die before uterine implantation (4), but liver-specific FAS knock-out mice (5) have decreased expression of fatty acid oxidation genes (classic targets of PPAR␣ signaling) and a phenotype resembling PPAR␣-deficient mice (6). Pharmacological activation of PPAR␣ reverses these features, suggesting that FAS generates an endogenous ligand for PPAR␣, and this FAS-dependent molecule was recently identified as a discrete phosphatidylcholine species (7). FAS also triggers PPAR␣ signaling in the hypothalamus (8) and in macrophages (9), raising the possibility that molecules generated by this enzyme are necessary for activating fatty acid metabolism, even in fatty acid-dependent tissues, such as the heart.Myocardial reliance on fatty acids as an energy source...

show abstract

“…FAS was also increased in the hearts of heartspecific TRAF2 transgenic mice (Fig. 9B) with inflammationmediated heart failure (19,56).…”

Section: Echo Parameter Control Faskardmentioning

confidence: 90%

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Razani

Zhang

Schulze

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…163 Conversely, overexpression of TNF␣ (at low levels) or TRAF2 on a wild type background ameliorates myocardial damage. 164 In the case of TRAF2, this is associated with NF-B activation. These observations suggest that the survival arm of the death receptor pathway can limit myocardial infarction during ischemia/reperfusion.…”

Section: Myocardial Infarctionmentioning

confidence: 99%

Programmed Necrosis, Not Apoptosis, in the Heart

Kung

Konstantinidis

Kitsis

2011

Circulation Research

248

208

View full text Add to dashboard Cite

Abstract:It is well known that apoptosis is an actively mediated cell suicide process. In contrast, necrosis, a morphologically distinct form of cell death, has traditionally been regarded as passive and unregulated. Over the past decade, however, experiments in Caenorhabditis elegans and mammalian cells have revealed that a significant proportion of necrotic death is, in fact, actively mediated by the doomed cell. Although a comprehensive understanding of necrosis is still lacking, some key molecular events have come into focus. Cardiac myocyte apoptosis and necrosis are prominent features of the major cardiac syndromes. Accordingly, the recognition of necrosis as a regulated process mandates a reexamination of cell death in the heart. This review discusses pathways that mediate programmed necrosis, how they intersect with apoptotic pathways, roles of necrosis in heart disease, and new therapeutic opportunities that the regulated nature of necrosis presents. (Circ Res. 2011;108:1017-1036.) Key Words: cell death Ⅲ necrosis Ⅲ apoptosis Ⅲ myocardial infarction Ⅲ heart failure A s recently as 30 years ago, cell death was viewed as a passive and unregulated process. Irreversible cellular injury (from physical/chemical/biological insults) was thought to kill solely by overwhelming cellular homeostasis. In this model, the cell was merely the recipient of damage and not a participant in its own demise. Unexplained by this paradigm, however, were the highly reproducible deaths of specific cells during the development of multiple organisms. In fact, these developmental cell deaths (termed "programmed cell death") had long been recognized but remained poorly understood. Studies in Caenorhabditis elegans showed that a relatively small network of genes (ced-9-|ced-43ced-3) regulates the deletion of a specific 131 cells during development. 1,2 These experiments provided the first evidence that any form of cell death was actively mediated. Subsequent work demonstrated that these genes had been conserved for more than 600 million years of evolution to humans. The orthologs of ced-9, ced-4, and ced-3 are, respectively, the bcl-2 (B-cell lymphoma 2) family, apaf-1 (apoptotic protease activating factor-1), and the caspase family. 3 Moreover, not only do these genes regulate developmental cell deaths in mammals, they also control the deaths of postnatal cells by a specific process termed apoptosis (discussed below). Taken together, these observations establish that cells often die through active mechanisms that have been highly conserved through evolution.Research more than the past 2 decades has built on these observations to produce a relatively mature understanding of the pathways that mediate apoptosis. These include an intrinsic pathway, which is conserved back to C elegans, that uses mitochondria and endoplasmic reticulum; and an extrinsic pathway that involves cell surface death receptors. These pathways are critical in the regulation of apoptosis. 3 Apoptosis is characterized by cell shrinkage and fragmentation into membra...

show abstract

“…However, etanercept failed to reduce death or hospitalization in phase III trials of ~1,500 heart failure patients (12). Infliximab, a chimeric monoclonal antibody against TNFα, also failed to improve cardiac function in patients with moderate-to-severe heart failure, and actually worsened clinical symptoms (13), suggesting a protective role for TNFα in the heart (14).…”

Section: Introductionmentioning

confidence: 99%

Targeting Inflammation in Heart Failure with Histone Deacetylase Inhibitors

McKinsey

2011

Mol Med

View full text Add to dashboard Cite

Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure.

show abstract

The Cytoprotective Effects of Tumor Necrosis Factor Are Conveyed Through Tumor Necrosis Factor Receptor–Associated Factor 2 in the Heart

Cited by 57 publications

References 37 publications

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Fatty Acid Synthase Modulates Homeostatic Responses to Myocardial Stress

Programmed Necrosis, Not Apoptosis, in the Heart

Targeting Inflammation in Heart Failure with Histone Deacetylase Inhibitors

Contact Info

Product

Resources

About