Histamine‐3 Receptor Activation Reduces Cardiac Fibrosis Through Direct Inhibition of Collagen Processing in Cardiac Fibroblasts

BACKGROUND AND PURPOSE: Fibrosis is a major contributor to diastolic dysfunction that underlies cardiac disease, such as heart failure with preserved ejection fraction. We previously established that exogenous histamine-3 receptor activation inhibits cardiac fibrosis in angiotensin II-infused mice. The present study aimed to determine the cellular mechanisms underlying the antifibrotic effect of the histamine-3 receptor, with a focus on cardiac fibroblasts. EXPERIMENTAL APPROACH: 8-week-old male wild-type C57BL/6J mice underwent saline or angiotensin II (Ang II, 1500 ng/kg/min) infusion with or without concomitant treatment with the histamine-3 receptor agonist, imetit dihydrobromide (40 mg/kg/day) for 7 days. Left ventricles were assessed for cardiac function, fibrosis, and hypertrophy. Proteomic analysis was performed to assess proteomic profiles between groups. Primary mouse cardiac fibroblast cultures were treated with TGF-β1 (30 ng/mL) and Imetit (300 nM) to assess collagen transcription, release, retention, and cellular signaling mechanisms. KEY RESULTS: Exogenous histamine-3 receptor activation with Imetit inhibited cardiac fibrosis and cardiomyocyte hypertrophy in Ang II-infused mice. Proteomic analysis identified distinct left ventricle proteomic profiles between Saline and Ang II mice. Imetit inhibited collagen I release, while promoting migration and intracellular collagen I retention in TGF-β1-treated mouse cardiac fibroblasts, potentially by inhibiting HSP-47 and reducing the phosphorylation of P38 MAP kinase. CONCLUSION AND IMPLICATIONS: Histamine-3 receptor activation inhibits cardiac fibrosis through a proposed mechanism involving collagen retention by cardiac fibroblasts, thereby, reducing released collagen. This study provides key insights into the histamine-3 receptor as a potential therapeutic target for cardiac fibrosis.