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.

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