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

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2705-2718
Number of pages	14
Journal	Journal of the American College of Cardiology
Volume	73
Issue number	21
DOIs	https://doi.org/10.1016/j.jacc.2019.02.074
State	Published - Jun 4 2019

Keywords

Alport syndrome
HFpEF
OGDHL
hiPS-CM
mitochondria
osteopontin

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacc.2019.02.074

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Yousefi, K., Irion, C. I., Takeuchi, L. M., Ding, W., Lambert, G., Eisenberg, T., Sukkar, S., Granzier, H. L., Methawasin, M., Lee, D. I., Hahn, V. S., Kass, D. A., Hatzistergos, K. E., Hare, J. M., Webster, K. A., & Shehadeh, L. A. (2019). Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway. Journal of the American College of Cardiology, 73(21), 2705-2718. https://doi.org/10.1016/j.jacc.2019.02.074

Yousefi, K, Irion, CI, Takeuchi, LM, Ding, W, Lambert, G, Eisenberg, T, Sukkar, S, Granzier, HL, Methawasin, M, Lee, DI , Hahn, VS , Kass, DA, Hatzistergos, KE, Hare, JM, Webster, KA & Shehadeh, LA 2019, 'Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway', Journal of the American College of Cardiology, vol. 73, no. 21, pp. 2705-2718. https://doi.org/10.1016/j.jacc.2019.02.074

@article{9e44b0c3fa26449f8743435ae74c50a8,

title = "Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway",

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",

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

note = "Publisher Copyright: {\textcopyright} 2019 American College of Cardiology Foundation",

year = "2019",

month = jun,

day = "4",

doi = "10.1016/j.jacc.2019.02.074",

language = "English (US)",

volume = "73",

pages = "2705--2718",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

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number = "21",

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TY - JOUR

T1 - Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

AU - Yousefi, Keyvan

AU - Irion, Camila I.

AU - Takeuchi, Lauro M.

AU - Ding, Wen

AU - Lambert, Guerline

AU - Eisenberg, Trevor

AU - Sukkar, Sarah

AU - Granzier, Henk L.

AU - Methawasin, Mei

AU - Lee, Dong I.

AU - Hahn, Virginia S.

AU - Kass, David A.

AU - Hatzistergos, Konstantinos E.

AU - Hare, Joshua M.

AU - Webster, Keith A.

AU - Shehadeh, Lina A.

PY - 2019/6/4

Y1 - 2019/6/4

N2 - 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.

AB - 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.

KW - Alport syndrome

KW - HFpEF

KW - OGDHL

KW - hiPS-CM

KW - mitochondria

KW - osteopontin

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DO - 10.1016/j.jacc.2019.02.074

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SN - 0735-1097

VL - 73

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JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

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ER -

Osteopontin Promotes Left Ventricular Diastolic Dysfunction Through a Mitochondrial Pathway

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