Research ArticleCardiology Open Access | 10.1172/JCI147120

Nolan T. Carew,1,2 Heidi M. Schmidt,1,2 Shuai Yuan,1 Joseph C. Galley,1,2 Robert Hall,1,2 Helene M. Altmann,1 Scott A. Hahn,1 Megan P. Miller,1 Katherine C. Wood,1,3 Bethann Gabris,4 Margaret C. Stapleton,5 Sean Hartwick,5 Marco Fazzari,2 Yijen L. Wu,5 Mohamed Trebak,1,2 Brett A. Kaufman,1,4 Charles F. McTiernan,1,4 Francisco J. Schopfer,1,2 Placido Navas,6 Patrick H. Thibodeau,7 Dennis M. McNamara,4 Guy Salama,1,4 and Adam C. Straub1,2,8

1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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1Heart, Lung, Blood and Vascular Medicine Institute,

2Department of Pharmacology and Chemical Biology,

3Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, and

4Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

5Department of Developmental Biology and Rangos Research Center Animal Imaging Core, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

6Andalusian Center for Developmental Biology and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain.

7Department of Microbiology and Molecular Genetics and

8Center for Microvascular Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Address correspondence to: Adam C. Straub, University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, Pennsylvania 15216, USA. Phone: 412.648.7097; Email: astraub@pitt.edu.

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Published September 15, 2022 - More info

Published in Volume 132, Issue 18 on September 15, 2022
J Clin Invest. 2022;132(18):e147120. https://doi.org/10.1172/JCI147120.
© 2022 Carew et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published September 15, 2022 - Version history
Received: January 4, 2021; Accepted: July 19, 2022 View PDF Abstract

Sudden cardiac death (SCD) in patients with heart failure (HF) is allied with an imbalance in reduction and oxidation (redox) signaling in cardiomyocytes; however, the basic pathways and mechanisms governing redox homeostasis in cardiomyocytes are not fully understood. Here, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to regulate redox signaling in erythrocytes and vascular cells, is essential for cardiomyocyte function. Using a conditional cardiomyocyte-specific CYB5R3-knockout mouse, we discovered that deletion of CYB5R3 in male, but not female, adult cardiomyocytes causes cardiac hypertrophy, bradycardia, and SCD. The increase in SCD in CYB5R3-KO mice is associated with calcium mishandling, ventricular fibrillation, and cardiomyocyte hypertrophy. Molecular studies reveal that CYB5R3-KO hearts display decreased adenosine triphosphate (ATP), increased oxidative stress, suppressed coenzyme Q levels, and hemoprotein dysregulation. Finally, from a translational perspective, we reveal that the high-frequency missense genetic variant rs1800457, which translates into a CYB5R3 T117S partial loss-of-function protein, associates with decreased event-free survival (~20%) in Black persons with HF with reduced ejection fraction (HFrEF). Together, these studies reveal a crucial role for CYB5R3 in cardiomyocyte redox biology and identify a genetic biomarker for persons of African ancestry that may potentially increase the risk of death from HFrEF.

Introduction

The healthy heart requires a highly synchronized series of reduction and oxidation (redox) reactions to support the electrical and mechanical demands of beating cardiomyocytes (1). In the aging population, the incidence of heart failure (HF) and sudden cardiac death (SCD) escalates and can be traced, in part, to disturbed redox equilibrium and its sequelae: impaired mitochondrial function and metabolism (2–4), oxidative stress (5), Ca2+ mishandling (6), and ventricular fibrillation (VF) (2, 7). Although substantial evidence points toward redox imbalance as an initiator of HF and SCD, the basic mechanisms that maintain redox equilibrium in healthy cardiomyocytes are not fully understood.

Cytochrome b5 reductase 3 (CYB5R3), also known as methemoglobin reductase, is a flavoprotein known for catalyzing 1-electron transfer reactions using reduced NADH as an electron donor. CYB5R3 controls diverse biological functions that are modulated partly by its subcellular compartmentalization on the outer mitochondrial membrane facing the cytosol, the endoplasmic reticulum, and the plasma membrane (8–10). Functionally, membrane-associated CYB5R3 exerts antioxidant properties by modulating plasma membrane coenzyme Q (CoQ) reduction (11–13), heme iron reduction (14–16), elongation and desaturation of fatty acids (17), cholesterol biosynthesis (18), and drug metabolism (19, 20), while the soluble form of CYB5R3 reduces RBC methemoglobin (21, 22). Humans with insufficient CYB5R3 activity suffer from recessive hereditary methemoglobinemia, an incurable disease with a clinical presentation of severe neurological complications and early childhood death (23, 24). While the importance of human CYB5R3 function to development is evident, the significance of CYB5R3 in the cardiovascular system and its potential in human cardiovascular disease has not been fully elucidated.

In the vascular wall, CYB5R3 regulates the redox state of α globin in small artery and arteriolar endothelial cells, controlling nitric oxide (NO) diffusion to vascular smooth muscle cells (VSMCs) (14, 15, 25, 26). More recently, we demonstrated that CYB5R3 governs the soluble guanylyl cyclase (sGC) heme redox state to control intracellular cyclic GMP (cGMP) levels in VSMCs (27, 28). While new functional pathways for CYB5R3 are under investigation, no reports have defined the significance of CYB5R3 in cardiomyocytes or the translational impact of modulating CYB5R3 activity in humans with heart disease. Based on the available evidence, we hypothesized that CYB5R3 expression and activity contribute to redox homeostasis in healthy cardiomyocytes and that decreased CYB5R3 function may lead to worse outcomes in patients with HF.

Results

Cardiac hypertrophy increases CYB5R3 expression. To determine whether cardiac hypertrophy and HF cause changes in CYB5R3 expression, we subjected C57BL6/J male mice to transverse aortic constriction (TAC). TAC caused a significant increase in left ventricular (LV) mass, LV anterior wall thickness, and heart weight–to–body weight ratio at 7, 14, and 27 days after TAC, despite no changes in peak aortic valve velocity changes (Supplemental Figure 1, A