Numerous aspects of cardiovascular physiology (e.g., heart rate, blood pressure) and pathology (e.g., myocardial infarction and sudden cardiac death) exhibit time-of-day-dependency. In association ...with day-night differences in energetic demand and substrate availability, the healthy heart displays remarkable metabolic flexibility through temporal partitioning of the metabolic fate of common substrates (glucose, lipid, amino acids). The purpose of this review is to highlight the contribution that circadian clocks provide toward 24-hr fluctuations in cardiac metabolism and to discuss whether attenuation and/or augmentation of these metabolic rhythms through adjustment of nutrient intake timing impacts cardiovascular disease development.
The post-translational modification of serine and threonine residues of proteins by O-linked N-acetylglucosamine (O-GlcNAc) regulates diverse cellular processes in the cardiovascular system. ...UDP-GlcNAc is a substrate for O-GlcNAc transferase, which catalyzes the attachment of O-GlcNAc to proteins. O-GlcNAcase catalyzes the removal of O-GlcNAc from proteins. UDP-GlcNAc is the end product of the hexosamine biosynthesis pathway, which is regulated primarily by glucose-6-phosphate-Glutamine:fructose-6-phosphate amidotransferase (GFAT). GFAT catalyzes the formation of glucosamine-6-phosphate from fructose-6-phosphate and glutamine. Whereas O-GlcNAc is essential for cell viability, sustained increases in O-GlcNAc levels have been implicated in the etiology of many chronic diseases and is associated with glucose toxicity and diabetic complications in various organs including the cardiovascular system. This review provides an overview of the regulation of protein O-GlcNAcylation followed by a discussion of potential mechanisms by which dysregulation in O-GlcNAc cycling contributes to the adverse effects of diabetes on the cardiovascular system.
Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a ...temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as to determine the pathologic consequences of chronic disruption of this circadian clock component. To address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 Bdh1) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase Pik3r1) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in life span. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.
Fatty acids and glucose are the main substrates for myocardial energy provision. Under physiologic conditions, there is a distinct and finely tuned balance between the utilization of these ...substrates. Using the non-ischemic heart as an example, we discuss that upon stress this substrate balance is upset resulting in an over-reliance on either fatty acids or glucose, and that chronic fuel shifts towards a single type of substrate appear to be linked with cardiac dysfunction. These observations suggest that interventions aimed at re-balancing a tilted substrate preference towards an appropriate mix of substrates may result in restoration of cardiac contractile performance. Examples of manipulating cellular substrate uptake as a means to re-balance fuel supply, being associated with mended cardiac function underscore this concept. We also address the molecular mechanisms underlying the apparent need for a fatty acid–glucose fuel balance. We propose that re-balancing cellular fuel supply, in particular with respect to fatty acids and glucose, may be an effective strategy to treat the failing heart.
Although empagliflozin was shown to profoundly reduce cardiovascular events in diabetic patients and blunt the decline in cardiac function in nondiabetic mice with established heart failure (HF), the ...mechanism of action remains unknown.
We treated 2 rodent models of HF with 10 mg/kg per day empagliflozin and measured activation of the NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome in the heart. We show for the first time that beneficial effects of empagliflozin in HF with reduced ejection fraction (HF with reduced ejection fraction HFrEF; n=30-34) occur in the absence of changes in circulating ketone bodies, cardiac ketone oxidation, or increased cardiac ATP production. Of note, empagliflozin attenuated activation of the NLRP3 inflammasome and expression of associated markers of sterile inflammation in hearts from mice with HFrEF, implicating reduced cardiac inflammation as a mechanism of empagliflozin that contributes to sustained function in HFrEF in the absence of diabetes mellitus. In addition, we validate that the beneficial cardiac effects of empagliflozin in HF with preserved ejection fraction (HFpEF; n=9-10) are similarly associated with reduced activation of the NLRP3 inflammasome. Lastly, the ability of empagliflozin to reduce inflammation was completely blunted by a calcium (Ca
) ionophore, suggesting that empagliflozin exerts its benefit upon restoring optimal cytoplasmic Ca
levels in the heart.
These data provide evidence that the beneficial cardiac effects of empagliflozin are associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a Ca
-dependent manner and hence may be beneficial in treating HF even in the absence of diabetes mellitus.
The formation of traditional ionic materials occurs principally via joint accumulation of both anions and cations. Herein, we describe a previously unreported phenomenon by which macroscopic ...liquid-like thin layers with tunable self-organization properties form through accumulation of stable complex ions of one polarity on surfaces. Using a series of highly stable molecular anions we demonstrate a strong influence of the internal charge distribution of the molecular ions, which is usually shielded by counterions, on the properties of the layers. Detailed characterization reveals that the intrinsically unstable layers of anions on surfaces are stabilized by simultaneous accumulation of neutral molecules from the background environment. Different phases, self-organization mechanisms and optical properties are observed depending on the molecular properties of the deposited anions, the underlying surface and the coadsorbed neutral molecules. This demonstrates rational control of the macroscopic properties (morphology and size of the formed structures) of the newly discovered anion-based layers.
Shift of myocardial substrate preference has been observed in many chronic diseases such as diabetes and heart failure. This study was undertaken to elucidate the mechanisms underlying the chronic ...substrate switch in adult hearts and to determine the functional consequences of the switch.
Transgenic mice with cardiac-specific overexpression of the insulin-independent glucose transporter GLUT1 (TG) were used to increase intracellular glucose in cardiac myocytes. A high-fat diet was used to increase the fatty acid supply to the heart. High-fat diet induced a 40% increase in fatty acid oxidation in wild-type hearts, whereas glucose oxidation was decreased to 30% of the control. In contrast, glucose oxidation was >2-fold higher in TG hearts, and the high-fat diet failed to upregulate fatty acid oxidation in these hearts. Glucose induced changes in the expression of multiple metabolic genes, including peroxisome proliferator-activated receptor-alpha (decreased by 51%), 3-oxoacid CoA transferase (decreased by 67%), and acetyl-CoA carboxylase (increased by 4-fold), resulting in a remodeling of the metabolic network to favor a shift of substrate preference toward glucose. Although TG mice on a normal diet maintained normal cardiac energetics and function, the inability to upregulate myocardial fatty acid oxidation in TG mice fed a high-fat diet resulted in increased oxidative stress in the heart, activation of p38 mitogen-activated protein kinase, and contractile dysfunction.
We have demonstrated that chronic increases in myocardial glucose uptake and oxidation reduce the metabolic flexibility and render the heart susceptible to contractile dysfunction.
Increased Hepatic CD36 Expression Contributes to Dyslipidemia Associated With Diet-Induced Obesity
Debby P.Y. Koonen 1 ,
René L. Jacobs 2 ,
Maria Febbraio 3 ,
Martin E. Young 4 ,
Carrie-Lynn M. ...Soltys 1 ,
Huy Ong 5 ,
Dennis E. Vance 2 and
Jason R.B. Dyck 1
1 Cardiovascular Research Group, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton,
Alberta, Canada
2 CIHR Group on the Molecular and Cellular Biology of Lipids, Department of Biochemistry, Faculty of Medicine and Dentistry,
University of Alberta, Edmonton, Alberta, Canada
3 Department of Cell Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio
4 Baylor College of Medicine, USDA/ARS Children’s Nutrition Research Center, Houston, Texas
5 Faculty of Pharmacy and Department of Pharmacology, Faculty of Medicine, Université de Montreal, Montreal, Quebec, Canada
Address correspondence and reprint requests to Dr. Jason R.B. Dyck, 474 Heritage Medical Research Centre, University of Alberta,
Edmonton, Alberta, Canada, T6G 2S2. E-mail: jason.dyck{at}ualberta.ca
Abstract
OBJECTIVE— The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty
acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated
whether increased expression of a fatty acid transport protein (CD36) in the liver during DIO contributes to the dyslipidemia
that precedes development of type 2 diabetes.
RESEARCH DESIGN AND METHODS— We determined the effect DIO has on hepatic CD36 protein expression and the functional consequence of this in terms of hepatic
triglyceride storage and secretion. In addition, in vivo adenoviral gene delivery of CD36 to the livers of lean mice was performed
to determine if increased hepatic CD36 protein was sufficient to alter hepatic fatty acid uptake and triglyceride storage
and secretion.
RESULTS— During DIO, CD36 protein levels in the liver are significantly elevated, and these elevated levels correlate with increased
hepatic triglyceride storage and secretion. These alterations in liver lipid storage and secretion were also observed upon
forced expression of hepatic CD36 in the absence of DIO and were accompanied with a marked rise in hepatic fatty acid uptake
in vivo, demonstrating that increased CD36 expression is sufficient to recapitulate the aberrant liver lipid handling observed
in DIO.
CONCLUSIONS— Increased expression of hepatic CD36 protein in response to DIO is sufficient to exacerbate hepatic triglyceride storage and
secretion. As these CD36-mediated effects contribute to the dyslipidemia that often precedes the development of type 2 diabetes,
increased hepatic CD36 expression likely plays a causative role in the pathogenesis of type 2 diabetes.
ALT, alanine aminotransferase
BMIPP, 15-p-123Iiodophenyl-3-(R,S)-methyl pentadecanoic acid
DIO, diet-induced obesity
NEFA, nonesterified fatty acid
SPECT, single photon emission computed tomography
VLDL, very-low-density lipoprotein
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 29 August 2007. DOI: 10.2337/db07-0907.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted August 23, 2007.
Received July 3, 2007.
DIABETES
The androgen receptor (AR) pathway plays a central role in the development of castration-resistant prostate cancer (CRPC). The histone demethylase JMJD1A has been shown to regulate activities of AR ...and c-Myc transcription factors and promote prostate cancer progression. Here, we report that JMJD1A protein stability is controlled by the ubiquitin ligase STUB1. High levels of JMJD1A were strongly correlated with low STUB1 levels in human CRPC specimens. STUB1 inhibited AR activity, AR-V7 levels, and prostate cancer cell growth partly through degradation of JMJD1A. Furthermore, the acetyltransferase p300 acetylated JMJD1A at lysine (K) 421, a modification that recruits the BET family member BRD4 to block JMJD1A degradation and promote JMJD1A recruitment to AR targets. Increased levels of both total and K421-acetylated JMJD1A were observed in prostate cancer cells as they developed resistance to the AR antagonist enzalutamide. Treatment of prostate cancer cells with either p300 or BET inhibitors destabilized JMJD1A, and enzalutamide-resistant prostate cancer cells were more sensitive than parental cells to these inhibitors. Together, our findings identify a critical role for acetylation of JMJD1A in regulating JMJD1A stability and AR activity in CRPC. These newly identified mechanisms controlling JMJD1A protein stability provide potential druggable targets to encourage the development of additional therapies for advanced prostate cancer. SIGNIFICANCE: Identification of mechanisms regulating JMJD1A protein stability reveals new strategies to destabilize JMJD1A and concomitantly inhibit AR activities as potential prostate cancer therapy.
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