Regulation of DNA damage and transcriptional output in the vasculature through a cytoglobin-HMGB2 axis
Clinton Mathai,
Frances Jourd'heuil,
Le Gia Cat Pham,
Kurrim Gilliard,
Dennis Howard,
Joseph Balnis,
Ariel Jaitovich,
Sridar V. Chittur,
Mark Rilley,
Ruben Peredo-Wende,
Ibrahim Ammoura,
Sandra J. Shin,
Margarida Barroso,
Jonathan Barra,
Evgenia Shishkova,
Joshua J. Coon,
Reynold I. Lopez-Soler,
David Jourd'heuil
Affiliations
Clinton Mathai
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Frances Jourd'heuil
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Le Gia Cat Pham
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Kurrim Gilliard
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Dennis Howard
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Joseph Balnis
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA; Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA
Ariel Jaitovich
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA; Division of Pulmonary and Critical Care Medicine, Albany Medical College, Albany, NY, USA
Sridar V. Chittur
Center for Functional Genomics, Cancer Research Center, University at Albany, New York, 12144, USA
Mark Rilley
Division of Rheumatology, Department of Medicine, Samuel Stratton VA Medical Center, Albany, NY, 12208, USA
Ruben Peredo-Wende
Division of Rheumatology, Department of Medicine, Samuel Stratton VA Medical Center, Albany, NY, 12208, USA
Ibrahim Ammoura
Department of Pathology and Medicine, Albany Medical Center, Albany, NY, 12208, USA
Sandra J. Shin
Department of Pathology and Medicine, Albany Medical Center, Albany, NY, 12208, USA
Margarida Barroso
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Jonathan Barra
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
Evgenia Shishkova
National Center for Quantitative Biology of Complex Systems, Madison, WI, 53706, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, 53506, USA
Joshua J. Coon
Department of Pathology and Medicine, Albany Medical Center, Albany, NY, 12208, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, 53506, USA; Morgridge Institute for Research, Madison, WI, 53515, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI, 53506, USA
Reynold I. Lopez-Soler
Section of Renal Transplantation, Edward Hines VA Jr. Hospital, Hines, IL, 60141, USA; Department of Surgery, Division of Intra-Abdominal Transplantation, Stritch School of Medicine, Maywood, IL, 60153, USA
David Jourd'heuil
Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA; Corresponding author.
Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2.
