C-C Chemokine Receptor 5 Deficiency Impairs Cardiac and Metabolic Homeostasis, Driving Heart Failure with Preserved...

C-C chemokine receptor 5 (CCR5) regulates immune responses, inflammation, and tissue remodeling, but its baseline role in cardiac and metabolic homeostasis remains unclear. Using CCR5 knockout (KO) mice, we examined the effects of CCR5 deficiency on cardiac structure, function, and metabolism. CCR5 KO mice showed increased body-weight gain despite reduced energy expenditure and a shift in nutrient partitioning, indicating metabolic dysregulation. Cardiac analyses revealed reduced heart weight with hypertrophic cardiomyocytes and widened sarcomeres, together with increased apoptosis, evidenced by elevated plasma cardiac troponin I (cTnI) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positivity. Fibrosis was increased, with upregulation of collagen genes and greater collagen deposition, alongside heightened inflammation marked by increased tumor necrosis factor-α, monocyte chemoattractant protein-1, interleukin-1β (IL-1β), IL-6, and macrophage infiltration (CD68). Hemodynamically, CCR5 deficiency reduced load-independent contractility and increased chamber stiffness, as indicated by a steeper end-diastolic pressure-volume relationship. At the molecular level, calcium-handling proteins were altered, including increased sarco/endoplasmic reticulum Ca²+-ATPase 2 and ryanodine receptor 2, and higher troponin I phosphorylation at serine-43 (p-Ser43-TnI), consistent with reduced myofilament Ca²+ sensitivity. Collectively, these structural, molecular, and functional changes resemble heart failure with preserved ejection fraction (HFpEF). We conclude that CCR5 is a key regulator of baseline cardiometabolic homeostasis; its deficiency promotes maladaptive remodeling, inflammation, and apoptosis, yielding an HFpEF-like phenotype. Although CCR5 antagonism may mitigate inflammation and fibrosis in certain settings, genetic deletion and pharmacologic inhibition are not equivalent, and potential cardiac effects warrant cautious, context-specific therapeutic consideration.