Role of macrophages in regression of myocardial fibrosis following alleviation of left ventricular pressure overload

Abstract

Sustained hemodynamic pressure-overload(PO) produced by murine transverse aortic constriction(TAC) causes myocardial fibrosis; removal of TAC(unTAC) returns LV hemodynamic load to normal and results in significant, but incomplete regression of myocardial fibrosis. However, the cellular mechanisms that result in these outcomes have not been defined. 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-mediated partial, but incomplete, regression of myocardial fibrosis.

Catecholamine treatment induces reversible heart injury and cardiomyocyte gene expression

“…We did not find specific gene programs to be activated during the recovery period, suggesting that cardiomyocytes are drivers of fibrosis progression while its resolution is rather mediated by other cell types, e.g. macrophages [ 55 ]. Although the extent of regulation in response to ET1 was weaker than with IsoPE, gene expression changes induced by ET1 incompletely recovered after minipump removal.…”

Galanin Coordinates Macrophage-Associated Fibro-Inflammatory Response and Mitochondrial Integrity in Myocardial Infarction Reperfusion Injury

“…The inflammatory motif is a significant component in the progression of cardiac I/R injury [ 9 ]. In response to myocardial I/R injury, macrophages, immune cells that are widely distributed in cardiac tissues, rapidly enter the area of the lesions and release effector factors, initiating the inflammatory reaction [ 6 ]. Macrophages represent a central component of the first-line immune riposte against cardiac I/R damage [ 9 ].…”

“…Macrophages represent a central component of the first-line immune riposte against cardiac I/R damage [ 9 ]. In a pathological scenario, macrophages display two phenotypes including a pro-inflammatory M1-like motif or anti-inflammatory M2-like phenotype [ 6 , 9 ]. Tissue macrophages have specific gene expression patterns and distinct sets of transcription factors that calibrate their properties and functions [ 25 ].…”

“…Myocardial fibrosis matures in a milieu of inflammatory cell infiltration and the degree of immune cell infiltration is directly associated with the severity of the tissue fibrosis [ 5 ]. Clinical and experimental observations have indicated that the accumulation of cardiac macrophages, the most abundant immune cells, correlates with the severity of the tissue fibrosis and cardiac injury [ 6 ]. The infiltration of inflammatory cells leads to cardiac fibrosis in murine models of cardiac remodeling [ 7 ].…”