Cardiac remodeling after myocardial infarction due to metabolic acidic stress: Transcription factor ICER and pH-sensing receptor GPR65 as modulators

M. Assmann (Mainz)¹, A. Hartl (Mainz)², J. Posma (Mainz)³, S. Finger (Mainz)⁴, M. Aluia (Mainz)⁴, P. Lurz (Mainz)⁵, T. Bohn (Mainz)⁶, T. Bopp (Mainz)⁶, P. Wenzel (Darmstadt)⁷, M. Molitor (Mainz)^8
1Centrum für Thrombose und Hämostase (CTH) AG Wenzel Mainz, Deutschland; ²University Medical Center Mainz Department of Cardiology Mainz, Deutschland; ³University Medical Center Mainz Center for Thrombosis und Hemostasis (CTH) Mainz, Deutschland; ⁴Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase Mainz, Deutschland; ⁵Universitätsmedizin der Johannes Gutenberg-Universität Mainz Kardiologie 1, Zentrum für Kardiologie Mainz, Deutschland; ⁶University Medical Center Mainz Institute of Immunology Mainz, Deutschland; ⁷Klinikum Darmstadt Medizinische Klinik I Darmstadt, Deutschland; ⁸Universitätsmedizin der Johannes Gutenberg-Universität Mainz Zentrum für Kardiologie Mainz, Deutschland

Background: Maladaptive cardiac remodeling following myocardial infarction (MI) causes cardiac dysfunction in ischemic heart disease, the leading global cause of death and a significant clinical challenge. This process crucially involves the innate immune system and inflammatory responses. Acidic microenvironments, prevalent in infarcted tissue, can modulate immune responses via pH-sensing G-protein coupled receptors (GPCRs), cyclic adenosine monophosphate (cAMP), and transcriptional regulators such as inducible cAMP early repressor (ICER). However, the physiological significance in post-MI repair and remodeling processes remains to be elucidated.
Methods: Mice with myeloid cell-specific knockout of ICER or the upstream pH-sensing GPCR GPR65 were subjected to chronic MI by left anterior descending artery (LAD) ligation. Cardiac function was assessed via echocardiography. Cardiac tissue was analyzed using qPCR, flow cytometry, and single-cell RNA sequencing of cardiac leukocytes. 
Results: qPCR and Single-cell RNA sequencing revealed high expression of acidosis response genes and pH-sensing receptors in cardiac myeloid cells post-MI. Myeloid cell-specific knockout of GPR65 or ICER exacerbated cardiac function after MI. Furthermore, ICER deficiency increased infiltration of inflammatory myeloid cells and reduced reparative TREM2+ macrophage abundance in the infarcted myocardium. However, adoptive transfer of ICER-expressing monocytes prior to MI induction restored wild-type cardiac function in ICER-deficient mice post-MI.
Conclusion: GPR65 and ICER regulate macrophage polarization towards a reparative phenotype, attenuating excessive inflammatory responses in maladaptive remodeling post-MI. These findings identify GPR65 and ICER as potential therapeutic targets for modulating immune and repair responses, thereby preventing maladaptive remodeling and heart failure in ischemic heart disease.