Background Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied. Methods and Results Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure-overload. Suppression of branched-chain amino acids (BCAAs) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids (BCKAs) was identified as a significant signature of metabolic reprogramming in mouse failing hearts, and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor KLF15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated BCKA directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction following pressure-overload. Conclusions BCAA catabolic defect is a metabolic hallmark of failing heart resulted from KLF15 mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease 1, 2, but the molecular basis is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (e.g. short or long QT syndromes, heart failure) 3-5 or pattern (e.g. Brugada syndrome) 6 of myocardial repolarization. Here we provide the first molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion channel expression and QT interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a novel clock-dependent oscillator, Krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito). 7 Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. In sum, these findings identify circadian transcription of ion channels as a novel mechanism for cardiac arrhythmogenesis.
SUMMARY Precise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia indusable factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NFκB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
Current therapies for diseases of heart muscle (cardiomyopathy) and aorta (aortopathy) include inhibitors of the renin-angiotensin system, β-adrenergic antagonists, and the statin class of cholesterol-lowering agents. These therapies have limited efficacy, as adverse cardiovascular events continue to occur with some frequency in patients taking these drugs. Although cardiomyopathy and aortopathy can coexist in a number of conditions (for example, Marfan's syndrome, acromegaly, pregnancy, and aging), pathogenetic molecular links between the two Copyright 2010 by the American Association for the Advancement of Science; all rights reserved. † To whom correspondence should be addressed. mukesh.jain2@case.edu. * These authors contributed equally to this work. SUPPLEMENTARY MATERIALwww.sciencetranslationalmedicine.org/cgi/content/full/2/26/26ra26/DC1 Fig. S1. Cardiovascular abnormalities in AngII-treated mice and cultured cells. Fig. S2. Baseline abnormalities in Klf15 −/− heart and aorta. Fig. S3. Cardiac mass and systolic blood pressure after AngII infusion. Fig. S4. Histologic parameters in aortas. Fig. S5. MMP-3 abundance in aortic smooth muscle. Fig. S6. p53 mRNA concentrations in heart and aortic tissue. Fig. S7. p300 abundance in hearts, curcumin administration protocol, and aortic morphometry after curcumin therapy. Table S1. Baseline cardiac parameters in Klf15 −/− and wild-type mice. Table S2. Cardiac parameters in Klf15 −/− and wild-type mice after AngII infusion. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript diseases remain poorly understood. We reasoned that identification of common molecular perturbations in these two tissues could point to therapies for both conditions. Here, we show that deficiency of the transcriptional regulator Kruppel-like factor 15 (Klf15) in mice leads to both heart failure and aortic aneurysm formation through a shared molecular mechanism. Klf15 concentrations are markedly reduced in failing human hearts and in human aortic aneurysm tissues. Mice deficient in Klf15 develop heart failure and aortic aneurysms in a p53-dependent and p300 acetyltransferase-dependent fashion. KLF15 activation inhibits p300-mediated acetylation of p53. Conversely, Klf15 deficiency leads to hyperacetylation of p53 in the heart and aorta, a finding that is recapitulated in human tissues. Finally, Klf15-deficient mice are rescued by p53 deletion or p300 inhibition. These findings highlight a molecular perturbation common to the pathobiology of heart failure and aortic aneurysm formation and suggest that manipulation of KLF15 function may be a productive approach to treat these morbid diseases.
Background-Altered electrical activation of the heart by pacing or disease induces profound ventricular electrical remodeling (VER), manifested electrocardiographically as T-wave memory and ultimately as deleterious mechanical remodeling from heterogeneous strain. Although T-wave memory is associated with altered expression of sarcolemmal ion channels, the biophysical mechanisms responsible for triggering remodeling of cardiac ion channels are unknown. Methods and Results-To test the hypothesis that mechanoelectrical feedback triggered by regional strain is a mechanism for VER, dogs (nϭ6) underwent 4 weeks of ventricular pacing to induce VER. Multisegment transmural optical action potential imaging of left ventricular wedges revealed profound and selective prolongation of action potential duration in late-activated (288Ϯ29 ms) compared with early-activated (250Ϯ9 ms) myocardial segments (PϽ0.05), providing the first experimental evidence that amplification of repolarization gradients between segments of left ventricle is the electrophysiological basis for T-wave memory. In vivo tagged magnetic resonance imaging revealed a 2-fold and preferential increase in circumferential strain in late-activated segments of myocardium, which exactly coincided with segments undergoing VER. VER could not be attributed to structural remodeling because it occurred without any histological evidence of cellular hypertrophy. Conclusions-The mechanism responsible for triggering remodeling of ion channel function in VER was locally enhanced circumferential strain. These data suggest a novel mechanoelectrical feedback mechanism for inducing physiological and potentially deleterious electrical heterogeneities in the heart. (Circulation. 2007;115:3145-3155.)
SUMMARY Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis still expressed endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor15.
The ability of skeletal muscle to enhance lipid utilization during exercise is a form of metabolic plasticity essential for survival. Conversely, metabolic inflexibility in muscle can cause organ dysfunction and disease. Although the transcription factor Kruppel-like factor 15 (KLF15) is an important regulator of glucose and amino acid metabolism, its endogenous role in lipid homeostasis and muscle physiology is unknown. Here we demonstrate that KLF15 is essential for skeletal muscle lipid utilization and physiologic performance. KLF15 directly regulates a broad transcriptional program spanning all major segments of the lipid-flux pathway in muscle. Consequently, Klf15-deficient mice have abnormal lipid and energy flux, excessive reliance on carbohydrate fuels, exaggerated muscle fatigue, and impaired endurance exercise capacity. Elucidation of this heretofore unrecognized role for KLF15 now implicates this factor as a central component of the transcriptional circuitry that coordinates physiologic flux of all three basic cellular nutrients: glucose, amino acids, and lipids.fat | mitochondria | myocyte | zinc finger
Background-Although heart failure (HF) is closely associated with susceptibility to sudden cardiac death (SCD), the mechanisms linking contractile dysfunction to cardiac electrical instability are poorly understood. Cardiac alternans has also been closely associated with SCD, and has been linked to a mechanism for amplifying electrical heterogeneities in the heart. However, previous studies have focused on alternans in normal rather than failing myocardium.
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