Role of Macrophages in Regression of Myocardial Fibrosis Following Alleviation of Left Ventricular Pressure Overload

The objective was to determine temporal changes in myocardial macrophage phenotype in TAC and unTAC and determine whether macrophage depletion alters collagen degradation after unTAC. Myocardial macrophage abundance and phenotype were assessed by immunohistochemistry, flow cytometry, and gene expression by rt-PCR in control(non-TAC),2wkTAC,4wkTAC, and 2wk,4wk, and 6wkunTAC. Myocardial cytokine profiles and collagen degrading enzymes were determined by immunoassay and immunoblots. Initial collagen degradation were detected with collagen hybridizing peptide(CHP). At unTAC, macrophages were depleted with clodronate liposomes and endpoints measured at 2wkunTAC. Macrophage number had a defined temporal pattern: increased in 2wk and 4wkTAC, followed by increases at 2wkunTAC (over 4wkTAC), that then decreased at 4wk and 6wkunTAC. At 2wkunTAC, macrophage area was significantly increased and was regionally associated with CHP reactivity. Cytokine profiles in unTAC reflected a pro-inflammatory milieu versus the TAC-induced pro-fibrotic milieu. Single cell sequencing analysis of 2wkTAC versus 2 and 6wkunTAC revealed distinct macrophage gene expression profiles at each time point demonstrating unique macrophage populations in unTAC versus TAC myocardium. Clodronate liposome depletion at unTAC reduced CHP reactivity and decreased Cathepsin K and proMMP2. We conclude that temporal changes in number and phenotype of macrophages play a critical role in both TAC-induced development and unTAC-...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research