@article{fbd253a0e2a04b7a8a0b3af0e47b0066,
title = "Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure",
abstract = "Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.",
keywords = "BCAA, blood pressure, branched-chain amino acid, cardiac metabolism, cardiovascular metabolism, heart failure, hypertension, Mendelian randomization, metabolomics",
author = "Danielle Murashige and Jung, {Jae Woo} and Neinast, {Michael D.} and Levin, {Michael G.} and Qingwei Chu and Lambert, {Jonathan P.} and Garbincius, {Joanne F.} and Boa Kim and Atsushi Hoshino and Ingrid Marti-Pamies and McDaid, {Kendra S.} and Shewale, {Swapnil V.} and Emily Flam and Steven Yang and Emilia Roberts and Li Li and Morley, {Michael P.} and Bedi, {Kenneth C.} and Hyman, {Matthew C.} and Frankel, {David S.} and Margulies, {Kenneth B.} and Assoian, {Richard K.} and Elrod, {John W.} and Cholsoon Jang and Rabinowitz, {Joshua D.} and Zoltan Arany",
note = "Funding Information: We thank the University of Pennsylvania CVI Mouse Phenotyping Core for surgeries and echocardiography. Telemetry and metabolomics were supported by the University of Pennsylvania DRC Rodent Metabolic Phenotyping Core and Metabolomics Core ( NIH P30-DK19525 and S10-OD025098 ). Human heart tissue procurement was supported by R01 HL149891 and R01 HL105993 . We thank the Gift-of-Life Donor Program, Philadelphia, PA, who helped provide nonfailing heart tissue. D.M. was supported by NHLBI ( F30 HL142186-01A1 ) and the Blavatnik Family Foundation . M.D.N. was supported by NIH 5T32CA257957 . J.F.G. was supported by NIH F32HL151146 . M.G.L. was supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine , the NIH/NHLBI ( T32HL007843 ), and the Measey Foundation . E.F. was supported by NHLBI T32 HL 7954-20 . M.C.H. was supported by Leducq ( TNE FANTASY 19CV03 ). B.K. was supported by the ADA ( 1-18-PDF-153 ). E.R. and R.K.A. were supported by NIH AG162140 . C.J. was supported by the Edward Mallinckrodt Jr. Foundation . Z.A. was supported by NHLBI ( HL152446 ), the Department of Defense ( W81XWH18-1-0503 ), and Pfizer . Funding Information: We thank the University of Pennsylvania CVI Mouse Phenotyping Core for surgeries and echocardiography. Telemetry and metabolomics were supported by the University of Pennsylvania DRC Rodent Metabolic Phenotyping Core and Metabolomics Core (NIH P30-DK19525 and S10-OD025098). Human heart tissue procurement was supported by R01 HL149891 and R01 HL105993. We thank the Gift-of-Life Donor Program, Philadelphia, PA, who helped provide nonfailing heart tissue. D.M. was supported by NHLBI (F30 HL142186-01A1) and the Blavatnik Family Foundation. M.D.N. was supported by NIH 5T32CA257957. J.F.G. was supported by NIH F32HL151146. M.G.L. was supported by the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine, the NIH/NHLBI (T32HL007843), and the Measey Foundation. E.F. was supported by NHLBI T32 HL 7954-20. M.C.H. was supported by Leducq (TNE FANTASY 19CV03). B.K. was supported by the ADA (1-18-PDF-153). E.R. and R.K.A. were supported by NIH AG162140. C.J. was supported by the Edward Mallinckrodt Jr. Foundation. Z.A. was supported by NHLBI (HL152446), the Department of Defense (W81XWH18-1-0503), and Pfizer. D.M. M.D.N. and Z.A. designed the study. D.M. executed most experiments with help from M.D.N. J.W.J. and S.Y. Mass spectrometry was performed by C.J. and M.D.N. Mendelian randomization studies were done by M.G.L. Q.C. performed catheter placement surgery. J.P.L. performed BT2 study at Temple University. A.H. generated Bckdkfl/fl mouse. MI surgeries were performed by the Penn CVI Physiology Core (K.S.M.); echocardiography was performed by J.F.G. and the Penn CVI Physiology Core (S.V.S. and I.M.-P.). B.K. and E.R. performed the carotid artery constriction/dilation experiment. L.L. performed histological sectioning and staining. D.S.F. and M.C.H. recruited participants and collected arterial and coronary sinus blood samples. E.F. K.C.B. and K.B.M. procured and curated human cardiac tissue samples and associated clinical metadata; E.F. analyzed tissue metabolomics; and M.P.M. analyzed tissue RNA-seq. D.M. and Z.A. wrote the manuscript. All authors discussed the results and commented on the manuscript. Z.A. received consulting fees from Pfizer. J.W.E. received consulting fees, unassociated with this work, from Jannsen Pharmaceuticals and Mitobridge, Inc. J.D.R. is an advisor and stockholder in Colorado Research Partners, Empress Therapeutics, L.E.A.F. Pharmaceuticals, Bantam Pharmaceuticals, Barer Institute, and Rafael Holdings; a founder, director, and stockholder of Farber Partners, Serien Therapeutics, and Sofro Pharmaceuticals; a founder and stockholder in Toran Therapeutics; inventor of patents held by Princeton University; and a director of the Princeton University-PKU Shenzhen collaboration. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = nov,
day = "1",
doi = "10.1016/j.cmet.2022.09.008",
language = "English (US)",
volume = "34",
pages = "1749--1764.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "11",
}