Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

Keyvan Yousefi; Camila I Irion; Lauro M Takeuchi; Wen Ding; Guerline Lambert; Trevor Eisenberg; Sarah Sukkar; Henk L Granzier; Mei Methawasin; Dong I Lee; Virginia S Hahn; David A Kass; Konstantinos E Hatzistergos; Joshua M Hare; Keith A Webster; Lina A Shehadeh

doi:10.1016/j.jacc.2019.02.074

Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

J Am Coll Cardiol. 2019 Jun 4;73(21):2705-2718. doi: 10.1016/j.jacc.2019.02.074.

Authors

Keyvan Yousefi¹, Camila I Irion², Lauro M Takeuchi³, Wen Ding¹, Guerline Lambert², Trevor Eisenberg⁴, Sarah Sukkar⁴, Henk L Granzier⁵, Mei Methawasin⁵, Dong I Lee⁶, Virginia S Hahn⁶, David A Kass⁶, Konstantinos E Hatzistergos⁷, Joshua M Hare², Keith A Webster⁸, Lina A Shehadeh⁹

Affiliations

¹ Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
² Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
³ Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
⁴ Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
⁵ Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.
⁶ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
⁷ Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Department of Cell Biology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
⁸ Department of Molecular and Cellular Pharmacology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Vascular Biology Institute and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Leonard M. Miller School of Medicine, Miami, Florida.
⁹ Interdisciplinary Stem Cell Institute, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Department of Medicine, Division of Cardiology, University of Miami Leonard M. Miller School of Medicine, Miami, Florida; Vascular Biology Institute and Peggy and Harold Katz Family Drug Discovery Center, University of Miami Leonard M. Miller School of Medicine, Miami, Florida. Electronic address: LShehadeh@med.miami.edu.

Abstract

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.

Keywords: Alport syndrome; HFpEF; OGDHL; hiPS-CM; mitochondria; osteopontin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Validation Study

MeSH terms

Animals
Autoantigens / genetics
Collagen Type IV / genetics
Disease Models, Animal*
Fibrosis
Genetic Therapy
Heart Failure, Diastolic / etiology*
Heart Failure, Diastolic / metabolism
Heart Failure, Diastolic / pathology
Heart Failure, Diastolic / therapy
Ketoglutarate Dehydrogenase Complex / genetics
Ketoglutarate Dehydrogenase Complex / metabolism*
Mice
Mice, Knockout
Mitochondria / metabolism
Myocardium / metabolism
Myocardium / pathology
Nephritis, Hereditary / complications
Osteopontin / genetics
Osteopontin / metabolism*
Oxidative Stress
Ventricular Dysfunction, Left / etiology*
Ventricular Dysfunction, Left / metabolism

Substances

Autoantigens
Collagen Type IV
type IV collagen alpha3 chain
Osteopontin
Ketoglutarate Dehydrogenase Complex

Abstract

Publication types

MeSH terms

Substances

Grants and funding