Dr Aly Elezaby is an advanced heart failure and transplant cardiology fellow at Stanford University School of Medicine and a postdoctoral fellow in the lab of Dr Daria Mochly-Rosen. He attended college at the University of Arizona, where he studied molecular and cellular biology with a research focus on mechanisms of genome instability. He graduated from the MD-PhD program at Boston University, with a dissertation focus on the effects of nutrient excess on mitochondrial function and oxidative stress in the heart. He completed residency training in internal medicine and cardiovascular medicine fellowship at Stanford as part of the Translational Investigator Program. His current research focus is on the signaling pathways that modulate cardiac ischemia-reperfusion injury, with a particular focus on regulation of metabolism and mitochondrial function.
Postdoctoral Fellowship, Stanford University, Cardiovascular Medicine (2023)
Fellowship, Stanford University, Cardiovascular Medicine (2022)
Residency, Stanford University, Internal Medicine (2019)
MD, PhD, Boston University, Molecular Medicine (2017)
BS, University of Arizona, Molecular and Cellular Biology (2009)
A Selective Inhibitor of Cardiac Troponin I Phosphorylation by Delta Protein Kinase C (deltaPKC) as a Treatment for Ischemia-Reperfusion Injury.
Pharmaceuticals (Basel, Switzerland)
2022; 15 (3)
Myocardial infarction is the leading cause of cardiovascular mortality, with myocardial injury occurring during ischemia and subsequent reperfusion (IR). We previously showed that the inhibition of protein kinase C delta (deltaPKC) with a pan-inhibitor (deltaV1-1) mitigates myocardial injury and improves mitochondrial function in animal models of IR, and in humans with acute myocardial infarction, when treated at the time of opening of the occluded blood vessel, at reperfusion. Cardiac troponin I (cTnI), a key sarcomeric protein in cardiomyocyte contraction, is phosphorylated by deltaPKC during reperfusion. Here, we describe a rationally-designed, selective, high-affinity, eight amino acid peptide that inhibits cTnI's interaction with, and phosphorylation by, deltaPKC (psiTnI), and prevents tissue injury in a Langendorff model of myocardial infarction, ex vivo. Unexpectedly, we also found that this treatment attenuates IR-induced mitochondrial dysfunction. These data suggest that deltaPKC phosphorylation of cTnI is critical in IR injury, and that a cTnI/deltaPKC interaction inhibitor should be considered as a therapeutic target to reduce cardiac injury after myocardial infarction.
View details for DOI 10.3390/ph15030271
View details for PubMedID 35337069
Cardiovascular effects of immunosuppression agents.
Frontiers in cardiovascular medicine
2022; 9: 981838
Immunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions and solid organ transplants. Key drug classes, namely calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and purine synthesis inhibitors, have direct effects on the structure and function of the heart and vascular system. In the heart, immunosuppressive agents modulate cardiac hypertrophy, mitochondrial function, and arrhythmia risk, while in vasculature, they influence vessel remodeling, circulating lipids, and blood pressure. The aim of this review is to present the preclinical and clinical literature examining the cardiovascular effects of immunosuppressive agents, with a specific focus on cyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate, and azathioprine.
View details for DOI 10.3389/fcvm.2022.981838
View details for PubMedID 36211586
- Iron Deficiency as a Potential Modulator of Subclinical Deficiencies in Cardiac Performance and Exercise Capacity. Journal of cardiac failure 2021; 27 (7): 822-824
- ABCB10 deletion in cardiomyocytes leads to mitochondrial dysfunction and early death ELSEVIER SCIENCE INC. 2018: S22
Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease.
Journal of the American Heart Association
2016; 5 (1)
Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD.Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium.Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103.
View details for DOI 10.1161/JAHA.115.002555
View details for PubMedID 26755553
View details for PubMedCentralID PMC4859372
Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.
Journal of molecular and cellular cardiology
2015; 79: 275–83
Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid-induced MHD.Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure/function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial-targeted catalase.FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKCα and PKCδ, and a decrease in phosphorylation of AKT and expression of CREB, PGC1α, PPARα and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice.Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function.
View details for DOI 10.1016/j.yjmcc.2014.12.001
View details for PubMedID 25497302
View details for PubMedCentralID PMC4301992
Partial Liver Kinase B1 (LKB1) Deficiency Promotes Diastolic Dysfunction, De Novo Systolic Dysfunction, Apoptosis, and Mitochondrial Dysfunction With Dietary Metabolic Challenge.
Journal of the American Heart Association
2015; 5 (1)
Myocardial hypertrophy and dysfunction are key features of metabolic heart disease due to dietary excess. Metabolic heart disease manifests primarily as diastolic dysfunction but may progress to systolic dysfunction, although the mechanism is poorly understood. Liver kinase B1 (LKB1) is a key activator of AMP-activated protein kinase and possibly other signaling pathways that oppose myocardial hypertrophy and failure. We hypothesized that LKB1 is essential to the heart's ability to withstand the metabolic stress of dietary excess.Mice heterozygous for cardiac LKB1 were fed a control diet or a high-fat, high-sucrose diet for 4 months. On the control diet, cardiac LKB1 hearts had normal structure and function. After 4 months of the high-fat, high-sucrose diet, there was left ventricular hypertrophy and diastolic dysfunction in wild-type mice. In cardiac LKB1 (versus wild-type) mice, high-fat, high-sucrose feeding caused more hypertrophy (619 versus 553 μm(2), P<0.05), the de novo appearance of systolic dysfunction (left ventricular ejection fraction; 41% versus 59%, P<0.01) with left ventricular dilation (3.6 versus 3.2 mm, P<0.05), and more severe diastolic dysfunction with progression to a restrictive filling pattern (E/A ratio; 5.5 versus 1.3, P=0.05). Myocardial dysfunction in hearts of cardiac LKB1 mice fed the high-fat, high-sucrose diet was associated with evidence of increased apoptosis and apoptotic signaling via caspase 3 and p53/PUMA (p53 upregulated modulator of apoptosis) and more severe mitochondrial dysfunction.Partial deficiency of cardiac LKB1 promotes the adverse effects of a high-fat, high-sucrose diet on the myocardium, leading to worsening of diastolic function and the de novo appearance of systolic dysfunction. LKB1 plays a key role in protecting the heart from the consequences of metabolic stress.
View details for DOI 10.1161/JAHA.115.002277
View details for PubMedID 26722122
View details for PubMedCentralID PMC4859355
High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II.
Journal of molecular and cellular cardiology
2015; 78: 165–73
Diet-induced obesity leads to metabolic heart disease (MHD) characterized by increased oxidative stress that may cause oxidative post-translational modifications (OPTM) of cardiac mitochondrial proteins. The functional consequences of OPTM of cardiac mitochondrial proteins in MHD are unknown. Our objective was to determine whether cardiac mitochondrial dysfunction in MHD due to diet-induced obesity is associated with cysteine OPTM.Male C57BL/6J mice were fed either a high-fat, high-sucrose (HFHS) or control diet for 8months. Cardiac mitochondria from HFHS-fed mice (vs. control diet) had an increased rate of H2O2 production, a decreased GSH/GSSG ratio, a decreased rate of complex II substrate-driven ATP synthesis and decreased complex II activity. Complex II substrate-driven ATP synthesis and complex II activity were partially restored ex-vivo by reducing conditions. A biotin switch assay showed that HFHS feeding increased cysteine OPTM in complex II subunits A (SDHA) and B (SDHB). Using iodo-TMT multiplex tags we found that HFHS feeding is associated with reversible oxidation of cysteines 89 and 231 in SDHA, and 100, 103 and 115 in SDHB.MHD due to consumption of a HFHS "Western" diet causes increased H2O2 production and oxidative stress in cardiac mitochondria associated with decreased ATP synthesis and decreased complex II activity. Impaired complex II activity and ATP production are associated with reversible cysteine OPTM of complex II. Possible sites of reversible cysteine OPTM in SDHA and SDHB were identified by iodo-TMT tag labeling. Mitochondrial ROS may contribute to the pathophysiology of MHD by impairing the function of complex II. This article is part of a Special Issue entitled "Mitochondria: From Basic Mitochondrial Biology to Cardiovascular Disease".
View details for DOI 10.1016/j.yjmcc.2014.07.018
View details for PubMedID 25109264
View details for PubMedCentralID PMC4268348
Overexpression of Catalase Diminishes Oxidative Cysteine Modifications of Cardiac Proteins.
2015; 10 (12): e0144025
Reactive protein cysteine thiolates are instrumental in redox regulation. Oxidants, such as hydrogen peroxide (H2O2), react with thiolates to form oxidative post-translational modifications, enabling physiological redox signaling. Cardiac disease and aging are associated with oxidative stress which can impair redox signaling by altering essential cysteine thiolates. We previously found that cardiac-specific overexpression of catalase (Cat), an enzyme that detoxifies excess H2O2, protected from oxidative stress and delayed cardiac aging in mice. Using redox proteomics and systems biology, we sought to identify the cysteines that could play a key role in cardiac disease and aging. With a 'Tandem Mass Tag' (TMT) labeling strategy and mass spectrometry, we investigated differential reversible cysteine oxidation in the cardiac proteome of wild type and Cat transgenic (Tg) mice. Reversible cysteine oxidation was measured as thiol occupancy, the ratio of total available versus reversibly oxidized cysteine thiols. Catalase overexpression globally decreased thiol occupancy by ≥1.3 fold in 82 proteins, including numerous mitochondrial and contractile proteins. Systems biology analysis assigned the majority of proteins with differentially modified thiols in Cat Tg mice to pathways of aging and cardiac disease, including cellular stress response, proteostasis, and apoptosis. In addition, Cat Tg mice exhibited diminished protein glutathione adducts and decreased H2O2 production from mitochondrial complex I and II, suggesting improved function of cardiac mitochondria. In conclusion, our data suggest that catalase may alleviate cardiac disease and aging by moderating global protein cysteine thiol oxidation.
View details for DOI 10.1371/journal.pone.0144025
View details for PubMedID 26642319
View details for PubMedCentralID PMC4671598
Impairment of the PPARa/PGC1a Axis Compromises Mitochondrial Biogenesis and Function in Hearts With Cardiomyocyte-Specific Fatty Acid Transport Protein 1 (FATP1) Overexpression
LIPPINCOTT WILLIAMS & WILKINS. 2013
View details for Web of Science ID 000332162907088
- Cardiac-Specific Fatty Acid Transport Protein 1 (FATP1) Overexpression Causes Decreased Mitochondrial Respiration, Increased Oxidative Stress and Activation of AMPK ELSEVIER SCIENCE INC. 2012: S159
Fusion of nearby inverted repeats by a replication-based mechanism leads to formation of dicentric and acentric chromosomes that cause genome instability in budding yeast.
Genes & development
2009; 23 (24): 2861–75
Large-scale changes (gross chromosomal rearrangements [GCRs]) are common in genomes, and are often associated with pathological disorders. We report here that a specific pair of nearby inverted repeats in budding yeast fuse to form a dicentric chromosome intermediate, which then rearranges to form a translocation and other GCRs. We next show that fusion of nearby inverted repeats is general; we found that many nearby inverted repeats that are present in the yeast genome also fuse, as does a pair of synthetically constructed inverted repeats. Fusion occurs between inverted repeats that are separated by several kilobases of DNA and share >20 base pairs of homology. Finally, we show that fusion of inverted repeats, surprisingly, does not require genes involved in double-strand break (DSB) repair or genes involved in other repeat recombination events. We therefore propose that fusion may occur by a DSB-independent, DNA replication-based mechanism (which we term "faulty template switching"). Fusion of nearby inverted repeats to form dicentrics may be a major cause of instability in yeast and in other organisms.
View details for DOI 10.1101/gad.1862709
View details for PubMedID 20008936
View details for PubMedCentralID PMC2800083