Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Abstract

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis

“…Similarly, gene ontology (GO) enrichment of nearest linked genes identified several terms associated with sepsis progression, including "TNF signaling pathway", "lymphadenopathy", and "thrombocytopenia" among hypo DMRs and "regulation of actin cytoskeleton" and "IL-3 signaling pathway" among hyper DMRs (Table EV3). Interestingly, hypo and hyper DMR-linked genes both demonstrated an enrichment for terms affiliated with G protein signaling, including "GTPase regulator activity", "CDC42 GTPase cycle", "RHO GTPase cycle", and "Ras signaling pathway", consistent with the known role of these pathways in sepsis-associated dysfunction (Lee et al, 2013b;Hahmeyer & da Silva Santos, 2021).…”

Role of RhoA and Rho-associated kinase in phenotypic switching of vascular smooth muscle cells: Implications for vascular function

“…Fasudil is also used in the treatment of glaucoma [191], pulmonary hypertension [190], and coronary vasospam [190]. Recently, other RhoA/ROCK inhibitors have been proposed as treatments for sepsis cardiovascular complications [192] and diabetic macular edema [193]. It has also been suggested to be beneficial in the management of Raynaud's disease [100,105,106,194] and multiple sclerosis [195].…”

Commonly disrupted pathways in brain and kidney in a pig model of systemic endotoxemia

“…Interestingly genes involved in signaling by Rho/Miro GTPases and RHOBTB3 are upregulated, while another set of genes involved in signaling by Rho GTPases and small GTPase-mediated signal transduction are downregulated (Additional files 1 , 4 : Fig S3 and Table S3). Bacterial toxins interfere with RhoGTPases resulting in modifications of epithelial and endothelial barriers that contribute to the dispersal of bacteria within the host [ 63 , 64 ]. Rho protein inhibition or activation has been associated with sepsis dysfunction according to the cellular system being evaluated [ 64 ].…”