| First Author | Eliezeck M | Year | 2026 |
| Journal | J Mol Cell Cardiol | Volume | 217 |
| Pages | 122-133 | PubMed ID | 42250623 |
| Mgi Jnum | J:391661 | Mgi Id | MGI:8351389 |
| Doi | 10.1016/j.yjmcc.2026.06.004 | Citation | Eliezeck M, et al. (2026) Cardiomyocyte-targeted Gi signaling promotes cardiac repair under sustained adrenergic stress in mice. J Mol Cell Cardiol |
| abstractText | Enhanced cholinergic signaling is associated with cardioprotection, with cardiomyocyte Gi activation via M2 muscarinic receptors proposed as a contributing mechanism. To test this therapeutic strategy, we engineered Myh6-Cre/hM4Di mice to selectively activate Gi signaling in cardiomyocytes (CM-Gi(+)) using DREADD technology. Gi pathway engagement was temporally controlled through clozapine-N-oxide (CNO) administration, and we evaluated its impact in a model of adrenergic-induced cardiomyopathy. In vitro, CNO reduced myocyte shortening in Myh6-Cre/hM4Di cardiomyocytes. It also suppressed isoproterenol (ISO)-induced contractility enhancement and phosphorylation of PKA target motifs, consistent with Gi activation. In vivo, a 7-day ISO regimen induced cardiac hypertrophy, inflammation, and expression of fibrosis markers, all prevented by CNO-driven CM-Gi(+) signaling. This intervention also preserved cardiomyocyte viability under ISO challenge in vitro and in vivo, underscoring its cytoprotective effects. To evaluate the therapeutic potential of this cell-targeted approach at a more advanced stage of injury, CNO treatment was initiated on day 4 of a 7-day ISO protocol, when cell death and inflammation are prominent. Echocardiographic, histological and flow cytometry analyses demonstrated that delayed CM-Gi(+) stimulation restored cardiac function and prevented macrophage accumulation. Contractility assessments confirmed normalization of myocyte function in ISO-treated mice, supporting the concept of cardiomyocyte recovery. Mechanistically, these beneficial effects were associated with reduced cardiac infiltration of CCR2(+) monocytes, key drivers of adverse remodeling. Our findings identify cardiomyocyte-specific Gi activation as a cytoprotective strategy that promotes myocardial repair under sustained adrenergic stress. This work lays the foundation for precision cell-targeted therapies aimed at modulating cholinergic/Gi signaling in the injured heart. |
