Ingramon-Depot Therapy in db/db Mice: The Impact on Local and Systemic Inflammation and Myocardial Remodeling

Introduction: Chronic systemic inflammation is a major driver of myocardial fibrosis in patients with metabolic syndrome; accordingly, db/db mice with impaired leptin signaling are widely used to model myocardial injury associated with obesity and hyperglycemia. This study investigates the impact of the peptide Ingramon, an antagonist of MCP-1 and interleukin-8, on systemic and local inflammation and myocardial remodeling in db/db mice. Methods: Sixteen-week-old female db/db mice were assigned to an experimental group that received subcutaneous injections of Ingramon encapsulated in PLGA microcapsules (Ingramon-depot; 30 mg/kg; n = 13) once every 2 weeks for 16 weeks or to a control group that received empty microcapsules as a placebo (n = 11). Transthoracic echocardiography was performed before and after treatment. At the end of the experiment, the mice were euthanized, and blood, adipose tissue, and heart tissue samples were collected for further analysis. Results: Ingramon-depot administration was associated with changes in adipose tissue leukocyte composition. The proportions of F4/80-positive macrophages tended to be lower, and the macrophage-to-T-cell ratio was significantly reduced. Morphological analysis showed significantly less cardiomyocyte granular degeneration/coagulative necrosis and myocardial fibrosis in Ingramon-depot-treated mice. Transcriptomic analysis of the myocardium revealed lower expression of neutrophil granule genes at the gene-set level in Ingramon-depot-treated mice. Conclusions: These findings suggest that Ingramon may exert cardioprotective effects in a murine model of diabetic cardiomyopathy; the underlying mechanisms, including a possible impact on inflammatory-cell recruitment, require further investigation.