Nucleus-mitochondria positive feedback loop formed by ERK5 S496 phosphorylation-mediated poly (ADP-ribose) polymerase activation provokes persistent pro-inflammatory senescent phenotype and accelerates coronary atherosclerosis after chemo-radiation
Sivareddy Kotla,
Aijun Zhang,
Masaki Imanishi,
Kyung Ae Ko,
Steven H. Lin,
Young Jin Gi,
Margie Moczygemba,
Sevinj Isgandarova,
Keri L. Schadler,
Caroline Chung,
Sarah A. Milgrom,
Jose Banchs,
Syed Wamique Yusuf,
Diana N. Amaya,
Huifang Guo,
Tamlyn N. Thomas,
Ying H. Shen,
Anita Deswal,
Joerg Herrmann,
Eugenie S. Kleinerman,
Mark L. Entman,
John P. Cooke,
Giovanni Schifitto,
Sanjay B. Maggirwar,
Elena McBeath,
Anisha A. Gupte,
Sunil Krishnan,
Zarana S. Patel,
Yisang Yoon,
Jared K. Burks,
Keigi Fujiwara,
Paul S. Brookes,
Nhat-Tu Le,
Dale J. Hamilton,
Jun-ichi Abe
Affiliations
Sivareddy Kotla
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author.
Aijun Zhang
Department of Medicine, Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, USA
Masaki Imanishi
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Kyung Ae Ko
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Steven H. Lin
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Young Jin Gi
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Margie Moczygemba
Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
Sevinj Isgandarova
Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
Keri L. Schadler
Department of Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Caroline Chung
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sarah A. Milgrom
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, University of Colorado Cancer Center, Aurora, CO, 80045, USA
Jose Banchs
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Syed Wamique Yusuf
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Diana N. Amaya
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Huifang Guo
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Tamlyn N. Thomas
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ying H. Shen
Division of Cardiothoracic Surgery, Baylor College of Medicine, Houston, TX, USA
Anita Deswal
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Joerg Herrmann
Cardio Oncology Clinic, Division of Preventive Cardiology, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
Eugenie S. Kleinerman
Department of Pediatric Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Mark L. Entman
Division of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX, USA
John P. Cooke
Department of Cardiovascular Sciences, Houston Methodist Research Institute, Houston, TX, USA
Giovanni Schifitto
Department of Neurology, University of Rochester, Rochester, NY, USA
Sanjay B. Maggirwar
Department of Microbiology, Immunology, and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA
Elena McBeath
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
Anisha A. Gupte
Department of Medicine, Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, USA
Sunil Krishnan
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, 32224, USA
Zarana S. Patel
KBR, NASA Johnson Space Center, Houston, TX, USA
Yisang Yoon
Department of Physiology, Medical College of Georgia, Augusta, GA, USA
Jared K. Burks
Department of Leukemia, Division of Center Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Keigi Fujiwara
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Paul S. Brookes
Department of Anesthesiology and Perioperative Medicine, University of Rochester, Rochester, NY, USA
Nhat-Tu Le
Division of Cardiovascular Sciences, Baylor College of Medicine, Houston, TX, USA
Dale J. Hamilton
Department of Medicine, Center for Bioenergetics, Houston Methodist Research Institute, Houston, TX, USA
Jun-ichi Abe
Department of Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author.
The incidence of cardiovascular disease (CVD) is higher in cancer survivors than in the general population. Several cancer treatments are recognized as risk factors for CVD, but specific therapies are unavailable. Many cancer treatments activate shared signaling events, which reprogram myeloid cells (MCs) towards persistent senescence-associated secretory phenotype (SASP) and consequently CVD, but the exact mechanisms remain unclear. This study aimed to provide mechanistic insights and potential treatments by investigating how chemo-radiation can induce persistent SASP. We generated ERK5 S496A knock-in mice and determined SASP in myeloid cells (MCs) by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. Candidate SASP inducers were identified by high-throughput screening, using the ERK5 transcriptional activity reporter cell system. Various chemotherapy agents and ionizing radiation (IR) up-regulated p90RSK-mediated ERK5 S496 phosphorylation. Doxorubicin and IR caused metabolic changes with nicotinamide adenine dinucleotide depletion and ensuing mitochondrial stunning (reversible mitochondria dysfunction without showing any cell death under ATP depletion) via p90RSK-ERK5 modulation and poly (ADP-ribose) polymerase (PARP) activation, which formed a nucleus-mitochondria positive feedback loop. This feedback loop reprogramed MCs to induce a sustained SASP state, and ultimately primed MCs to be more sensitive to reactive oxygen species. This priming was also detected in circulating monocytes from cancer patients after IR. When PARP activity was transiently inhibited at the time of IR, mitochondrial stunning, priming, macrophage infiltration, and coronary atherosclerosis were all eradicated. The p90RSK-ERK5 module plays a crucial role in SASP-mediated mitochondrial stunning via regulating PARP activation. Our data show for the first time that the nucleus-mitochondria positive feedback loop formed by p90RSK-ERK5 S496 phosphorylation-mediated PARP activation plays a crucial role of persistent SASP state, and also provide preclinical evidence supporting that transient inhibition of PARP activation only at the time of radiation therapy can prevent future CVD in cancer survivors.
