4-Methylumbelliferone Attenuates Macrophage Invasion and Myocardial Remodeling in Pressure-Overloaded Mouse Hearts

Abstract

Cardiac wall stress induces local and systemic inflammatory responses that are increasingly recognized as key modulators of extracellular matrix remodeling. Hyaluronic acid interacts with immune cells and mesenchymal cells thereby modulating profibrotic signals. Here we tested the hypothesis that 4-methylumbelliferone (4-MU), an inhibitor of hyaluronic acid synthesis, would attenuate inflammation and extracellular matrix remodeling of pressure-overloaded myocardium in C57BL/6J male mice fed with 4-MU and subjected to TAC (transverse aortic constriction) surgery. Flow cytometry of immune cells showed TAC-induced leukocytosis due to an increase of neutrophils and monocytes. 4-MU strongly attenuated both circulating and cardiac leukocyte numbers 3 days after TAC. In the hearts, 4-MU reduced the number of CCR2 − resident macrophages. At later time points, 4-MU also prevented the infiltration of heart tissue by bone marrow-derived circulating monocytes leading to reduced cardiac macrophage counts even 7 weeks after TAC. The long-term attenuation of macrophage-driven inflammation was associated with less myocardial fibrosis in 4-MU-treated compared with untreated mice. Unexpectedly, 4-MU also reduced the development of left ventricular hypertrophy and increased cardiac output after TAC without affecting blood pressure. The data demonstrate that 4-MU reduces both resident and invading cardiac macrophages and may be a promising agent to alleviate pressure-overload induced myocardial damage.

Macrophage Polarization in Left Ventricular Structural Remodeling Induced by Hypertension

“…Hackert et al . [ 26 ] found that expression of CCR-2, CCR-5, and C-X3-C motif chemokine receptor 1 (CX3CL1) increased in the heart, and monocytes were recruited into the heart tissue 3 days after TAC, while mRNA expression of chemotactic agents and adhesion molecules such as CX3CL1, CXCL1, and pro-inflammatory cytokine IL-1 was observed 7 weeks after TAC, indicating a shift towards the M1 phenotype in macrophages at this time point.…”

The Sweet Smell of Progress With Hyaluronan and Heart Failure

“…In this issue of Hypertension , Hackert et al 1 make the initial observation that HAS2 (hyaluronan synthase 2) expression is increased in the heart in response to transverse aortic constriction, a well-established experimental model of cardiac fibrosis and heart failure (HF). To evaluate the role of hyaluronan synthesis in adverse cardiac remodeling, the authors use 4-methylumbelliferone (4-MU), a naturally occurring coumarin that inhibits hyaluronan deposition purportedly through depletion of Uridine di-phosphate glucose A, which is required for hyaluronan formation.…”

“…Perhaps such a strategy could be pursued in addition to strategies, such as 4-MU. Either way, Hackert et al 1 remind us that there is a sweet smell of progress with 4-MU and biologically active sugars—we just need to make hyaluronan while the sun shines.…”

“…Not surprisingly, left ventricular contractile function was improved in 4-MU-treated mice compared with control. 1…”