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Epigenetic Signatures of Human Myocardium and Brown Adipose Tissue Revealed With medRxiv preprint doi: https://doi.org/10.1101/2020.12.06.20244814; this version posted December 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Epigenetic Signatures of Human Myocardium and Brown Adipose Tissue Revealed with Simultaneous Positron Emission Tomography and Magnetic Resonance of Class I Histone Deacetylases. 1David Izquierdo-Garcia, 1Jacob M. Hooker, 1Frederick A. Schroeder, 1Choukri Mekkaoui, 1Tonya M. Gilbert, 1Marcello Panagia, 2Cheryl Cero, 1Lindsey Rogers, 1Anisha Bhanot, 1Changning Wang, 2Aaron M. Cypess, 1,*Ciprian Catana, 1,3,*David E. Sosnovik. 1Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston MA 2Translational Physiology Section, Diabetes, Endocrinology, and Obesity Branch, NIDDK, National Institutes of Health, Bethesda MD 3Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston MA * Contributed Equally Correspondence: David E. Sosnovik, MD FACC Cardiovascular Research Center Massachusetts General Hospital and Harvard Medical School 149 13th St, Charlestown, MA 02129 Tel: (617) 724-1679 Email: [email protected] Word count: 6025 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.12.06.20244814; this version posted December 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Rationale: Histone deacetylases (HDACs) play a central role in cardiac hypertrophy and fibrosis in preclinical models. However, their impact in the human heart remains unknown. Objective: We aimed to image HDAC expression in the human heart in vivo with PET-MR (positron emission tomography and magnetic resonance) using [11C]Martinostat, a novel radiotracer targeted to class I HDACs. We further aimed to compare HDAC expression in the heart with its expression in skeletal muscle and brown/white adipose tissue (BAT/WAT). Methods and Results: The specificity and selectivity of [11C]Martinostat binding in the heart was assessed in non-human primates (n=2) by in vivo blocking studies and with an ex vivo cellular thermal shift assay (CETSA) of HDAC paralog stabilization by Martinostat. PET-MR imaging of [11C]Martinostat was performed in healthy volunteers (n=6) for 60 minutes to obtain time-activity curves of probe uptake and kinetics. qPCR of class I HDACs was performed in specimens of BAT obtained from patients (n=7) undergoing abdominal surgery and in specimens of human subcutaneous WAT (n=7). CETSA and the blocking studies demonstrated that Martinostat was specific for class I HDACs in the heart. HDAC density, measured by standardized uptake values of [11C]Martinostat, was 8 times higher in the myocardium than skeletal muscle (4.4 ± 0.6 vs. 0.54 ± 0.29, p<0.05) and also significantly higher in BAT than WAT (0.96 ± 0.29 vs. 0.17 ± 0.08, p<0.05). qPCR confirmed higher class I HDAC expression in BAT, particularly HDAC2 and HDAC3 (2.6 and 2.7-fold higher than WAT respectively, p<0.01). Conclusions: Class I HDAC expression in the human heart can be imaged in vivo and is dramatically higher than any other peripheral tissue, including skeletal muscle. The high levels of HDAC in the myocardium and BAT suggest that epigenetic regulation plays an important role in tissues with high energetic demands and metabolic plasticity. Keywords: Histone Deacetylase, Molecular Imaging, Heart, PET-MR, Brown Adipose, Myocardium medRxiv preprint doi: https://doi.org/10.1101/2020.12.06.20244814; this version posted December 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Introduction Histone deacetylases (HDACs) are a family of enzymes that, among other functions, catalyze the hydrolysis of acetyl-L-lysine to free L-lysine side chains in protein substrates. Certain members of the family operate within an epigenetic capacity by altering chromatin remodeling and thus gene transcription in mammalian cells.1 Three classes of zinc-dependent HDACs exist,2 and a subset in class I, HDAC paralogs 1, 2, and 3, have been strongly implicated with cardiovascular disease.3-8 Preclinical studies have shown that the inhibition of class I HDACs can prevent, and even reverse, left ventricular hypertrophy (LVH) and myocardial fibrosis.9-11 However, the role of HDACs in the adult human heart remains poorly defined and difficult to assess. In addition, the expression of HDAC in other metabolically active tissues, such as skeletal muscle and brown adipose tissue, has not been well characterized. HDAC expression in the brain and peripheral organs can be imaged in vivo with the positron emission tomography (PET) radiotracer, [11C]Martinostat.12, 13 Here, we aimed to use this radiotracer to assess relative HDAC expression in the human heart in vivo, and to determine how this compares to HDAC expression in other tissues with high energetic demands. Positron emission tomography and magnetic resonance (PET-MR) imaging of [11C]Martinostat uptake was therefore measured in the heart, bone marrow, skeletal muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) in 6 healthy volunteers. In addition, the mRNA expression of class I HDACs was assessed in specimens of BAT, acquired from 7 patients undergoing abdominal surgery. These studies, to the best of our knowledge, provide the first measurement of HDAC in human BAT and the first successful report of HDAC imaging in the human heart in vivo. medRxiv preprint doi: https://doi.org/10.1101/2020.12.06.20244814; this version posted December 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Materials and Methods [11C]Martinostat dynamics and regional distribution have been determined in the young, healthy human brain, where the tool appears sensitive and specific for HDAC expression.12-16 The binding of [11C]Martinostat to class I HDACs in the non-human primate myocardium was demonstrated in this study in three steps: 1) A cellular thermal shift assay (CETSA) was performed on post mortem myocardial specimens from the hearts of non-human primates, 2) the uptake of [11C]Martinostat in the myocardium of a non-human primate was blocked by pre- injection of the non-radioactive isotopalogue and, 3) the uptake of 11C-Martinostat in the myocardium was blocked by the infusion of a competitive inhibitor of class I/IIb HDACs (suberoylanilide hydroxamic acid, SAHA). All animal studies were performed under a protocol approved by our Institutional Animal Care and Use Committee. In addition to its distribution in non-human primates, the uptake dynamics of [11C]Martinostat were also determined in myocardium of healthy human volunteers. Cellular Thermal Shift Assay Myocardial tissue from non-human primates (Papio anubis, n=2) was removed from storage at - 80 oC, 50-100 mg was cut while frozen and sealed in a custom bag (~ 2.5 x 4 cm2) made from temperature stable plastic (Kapak by Ampak, 2.5 mm thickness), deeply frozen by submerging in liquid nitrogen for 5 min and manually pulverized for 20-30 sec between the flat side of an aluminum block and a 12 ounce hammer with a metal head, both pre-chilled on dry ice. Tissue was suspended by adding lysis buffer containing PBS, 0.15% NP-40, and a protease inhibitor cocktail (Roche 04693159001) at 50 mg/ml directly to the plastic bag. The tissue suspension was transferred to a 1.5 mL Eppendorf tube and homogenized with an electric pestle (2 min) then medRxiv preprint doi: https://doi.org/10.1101/2020.12.06.20244814; this version posted December 8, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . sonicated on ice at 50% power (Fisher Scientific Model CL-18) using thirty 1-second pulses with a 1 second interval between pulses. The lysate was triturated on ice with a disposable 5 mL syringe fitted with a 23 ga needle (10 passages, 2 min total) avoiding introduction of air/foam, then incubated with rotation at 4 °C for 20 min, and centrifuged at 18,000 x g at 4 °C for 20 min. Supernatant was collected and total protein concentration was measured using a bicinchoninic acid (BCA) protein assay (Pierce 23227). To determine the thermal stability of HDAC paralogs in myocardial tissue, lysate was heated in three degree increments from 34 °C to 69 °C for 3 min in a thermocycler and then cooled at 10 °C for 3 min. Aliquots were immediately centrifuged (18,000 x g at 4 °C) for 10 min. Supernatants were then collected, 3X SDS-PAGE loading buffer containing 125 mM DTT was added, samples were heated to a boil for 10 min, and western blotting was performed. Relative mean band intensity was plotted and fitted with the Boltzmann sigmoidal equation (Prism, Graphpad) to obtain melting temperatures (Tm). Based on the Tm, 60 °C was chosen for HDAC paralogs 1/2/6 assessment and 65°C was chosen for HDAC3 assessment in the concentration gradient CETSA.
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