Author + information
- Received November 24, 2018
- Revision received February 25, 2019
- Accepted February 26, 2019
- Published online May 27, 2019.
- Keyvan Yousefi, PharmDa,b,∗,
- Camila I. Irion, PhDb,c,∗,
- Lauro M. Takeuchi, DDSb,
- Wen Ding, PhDa,b,
- Guerline Lambert, MSb,c,
- Trevor Eisenberg, BSc,
- Sarah Sukkar, BSc,
- Henk L. Granzier, PhDd,
- Mei Methawasin, MD, PhD, BSd,
- Dong I. Lee, PhDe,
- Virginia S. Hahn, MDe,
- David A. Kass, MDe,
- Konstantinos E. Hatzistergos, PhDb,f,
- Joshua M. Hare, MDb,c,
- Keith A. Webster, PhDa,g and
- Lina A. Shehadeh, PhDb,c,g,∗ (, )@umiamimedicine
- aDepartment of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
- bInterdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
- cDepartment of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
- dDepartment of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona
- eDivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
- fDepartment of Cell Biology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
- gVascular Biology Institute and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Leonard M. Miller School of Medicine, Miami, Florida
- ↵∗Address for correspondence:
Dr. Lina A. Shehadeh, Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, 1501 NW 10th Avenue, Biomedical Research Building Room 818, Miami, Florida 33136.
Background Patients with chronic kidney disease (CKD) and coincident heart failure with preserved ejection fraction (HFpEF) may constitute a distinct HFpEF phenotype. Osteopontin (OPN) is a biomarker of HFpEF and predictive of disease outcome. We recently reported that OPN blockade reversed hypertension, mitochondrial dysfunction, and kidney failure in Col4a3−/− mice, a model of human Alport syndrome.
Objectives The purpose of this study was to identify potential OPN targets in biopsies of HF patients, healthy control subjects, and human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs), and to characterize the cardiac phenotype of Col4a3−/− mice, relate this to HFpEF, and investigate possible causative roles for OPN in driving the cardiomyopathy.
Methods OGDHL mRNA and protein were quantified in myocardial samples from patients with HFpEF, heart failure with reduced ejection fraction, and donor control subjects. OGDHL expression was quantified in hiPS-CMs treated with or without anti-OPN antibody. Cardiac parameters were evaluated in Col4a3−/− mice with and without global OPN knockout or AAV9-mediated delivery of 2-oxoglutarate dehydrogenase-like (Ogdhl) to the heart.
Results OGDHL mRNA and protein displayed abnormal abundances in cardiac biopsies of HFpEF (n = 17) compared with donor control subjects (n = 12; p < 0.01) or heart failure with reduced ejection fraction patients (n = 12; p < 0.05). Blockade of OPN in hiPS-CMs conferred increased OGDHL expression. Col4a3−/− mice demonstrated cardiomyopathy with similarities to HFpEF, including diastolic dysfunction, cardiac hypertrophy and fibrosis, pulmonary edema, and impaired mitochondrial function. The cardiomyopathy was ameliorated by Opn−/− coincident with improved renal function and increased expression of Ogdhl. Heart-specific overexpression of Ogdhl in Col4a3−/− mice also improved cardiac function and cardiomyocyte energy state.
Conclusions Col4a3−/− mice present a model of HFpEF secondary to CKD wherein OPN and OGDHL are intermediates, and possibly therapeutic targets.
↵∗ Drs. Yousefi and Irion contributed equally to this work.
This work was supported by the following grants (to Dr. Shehadeh): National Institute of Health (R56HL132209 and 1R01HL140468) and the Miami Heart Research Institute. The National Heart, Lung, and Blood Institute’s Gene Therapy Resource Program funded the AAV generation at the Penn Vector Core. Dr. Yousefi is a recipient of an American Heart Association (AHA) pre-doctoral fellowship (18PRE33960070). Dr. Ding is a recipient of a Sublett AHA pre-doctoral fellowship (15PRE22450019). Dr. Hahn is funded by the National Institutes of Health (NIH 2T32HL007227-41). Dr. Hatzistergos has ownership interest with Vestion Inc. Dr. Hare has ownership interest in Heart Genomics, Biscayne Pharma, Vestion, and Longeveron; has received research funding from the National Heart, Lung, and Blood Institute; and has received consultant/advisory fees from Longeveron and Vestion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received November 24, 2018.
- Revision received February 25, 2019.
- Accepted February 26, 2019.
- 2019 American College of Cardiology Foundation
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