Recurrent Adrenergic Stress Provokes Persistent Myocarditis in PD-1-Deficient Mice

Tomohiro Hayashi; Kenji Rowel Q Lim; Attila Kovacs; Douglas L Mann

doi:10.1016/j.jacbts.2023.07.012

Recurrent Adrenergic Stress Provokes Persistent Myocarditis in PD-1-Deficient Mice

JACC Basic Transl Sci. 2023 Sep 20;8(12):1503-1517. doi: 10.1016/j.jacbts.2023.07.012. eCollection 2023 Dec.

Authors

Tomohiro Hayashi^{1

2}, Kenji Rowel Q Lim¹, Attila Kovacs¹, Douglas L Mann¹

Affiliations

¹ Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
² Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe, Japan.

Abstract

It is unclear how the immune system initiates effective tissue repair responses without also simultaneously activating adaptive immune responses to self-antigens released by damaged or necrotic cells. We studied the role of repetitive adrenergic mediated stress on cardiac injury wild-type and programmed death-1-deficient (PD-1^-/-) mice treated with 3 intraperitoneal low doses of isoproterenol followed by an intraperitoneal injection of high-dose ISO 7 days later (ISO^primed/ISO^injury). Repetitive adrenergic stress in ISO^primed/ISO^injury PD-1^-/- mice resulted in a persistent dysregulated myocardial inflammatory response characterized by the expansion of autoreactive effector CD8⁺ T cells, increased cardiac hypertrophy, mild left ventricular dysfunction, and increased lethality when compared with ISO^primed/ISO^injury wild-type mice.

Keywords: immune checkpoints; inflammation; myocarditis; tissue injury.