AIMSCardiac fibrosis is characterized by aberrant collagen deposition in the heart. Macrophage polarization or infiltration is the main reason to accelerate the collagen deposition. We attempted to investigate the involvement of MKL1 in macrophages during the development of cardiac fibrosis.MATERIALS AND METHODSCardiac fibrosis is induced by myocardial infarction (MI). The MKL1^f/f mice were crossed to the Lyz2-cre mice to generate macrophage conditional MKL1 knockout mice (MKL1^ΔMφ). In addition, macrophage conditional MKL1 overexpression mice (MKL1^Mϕ-OE) were constructed by crossing Lyz2-cre mice to MKL1^{ΔN200-Rosa26} mice.KEY FINDINGSMKL1 expression was significantly increased in macrophages of both ischemic cardiomyopathy (ICM) patients and mice induced to develop myocardial infarction. Deletion of MKL1 in macrophages improved the heart function after MI-induced cardiac fibrosis. Consistently, MKL1^Mϕ-OE mice displayed more severe cardiac fibrosis and worsened heart function than the control mice after MI. Moreover, administration of a small-molecule MKL1 inhibitor CCG-1423 also decreased the collagen deposition after MI.SIGNIFICANCEOur data demonstrate that MKL1 in macrophages contributes to cardiac fibrosis pathogenesis and reinforce the notion that targeting MKL1 may yield effective antifibrotic therapeutics in the heart.

16 Oct 2024·The Journal of Infectious Diseases

Inhibition of RhoA Prevents Cryptococcus neoformans Capsule Glucuronoxylomannan-Stimulated Brain Endothelial Barrier Disruption

Article

Author: Munzen, Melissa E ; Saytoo, Durvinand ; Dores, Michael R ; Reguera-Gomez, Marta ; Enriquez, Vanessa ; Mathew, Cristian ; Minhas, Amanjeet ; Martinez, Luis R ; Charles-Niño, Claudia L

AbstractCryptococcus neoformans (Cn) is an opportunistic fungus that causes severe central nervous system (CNS) disease in immunocompromised individuals. Brain parenchyma invasion requires fungal traversal of the blood-brain barrier. In this study, we describe that Cn alters the brain endothelium by activating small GTPase RhoA, causing reorganization of the actin cytoskeleton and tight junction modulation to regulate endothelial barrier permeability. We confirm that the main fungal capsule polysaccharide glucuronoxylomannan is responsible for these alterations. We reveal a therapeutic benefit of RhoA inhibition by CCG-1423 in vivo. RhoA inhibition prolonged survival and reduced fungal burden in a murine model of disseminated cryptococcosis, supporting the therapeutic potential of targeting RhoA in the context of cryptococcal infection. We examine the complex virulence of Cn in establishing CNS disease, describing cellular components of the brain endothelium that may serve as molecular targets for future antifungal therapies to alleviate the burden of life-threatening cryptococcal CNS infection.

01 Aug 2024·American Journal of Physiology-Cell Physiology

Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1

Article

Author: Szászi, Katalin ; Connelly, Kim A. ; Rzepka, Mark F. ; Friedberg, Mark K. ; Venugopal, Shruthi ; Layne, Matthew D. ; Kofler, Michael ; Sri Theivakadadcham, Veroni S. ; Dan, Qinghong ; Kapus, András ; Wu, Brian

We show that expression of the RhoA regulator GEF-H1 is upregulated in tubular cells exposed to fibrogenic cytokines and in animal models of kidney and heart fibrosis. We identify a pathway wherein GEF-H1/RhoA-dependent MRTF activation through its noncanonical partner Sp1 upregulates GEF-H1. Our data reveal the existence of a positive feedback cycle that enhances Rho signaling through control of both GEF-H1 activation and expression. This feedback loop may play an important role in organ fibrosis.

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