RhoA and ROCK mediate histamine-induced vascular leakage and anaphylactic shock

Histamine-induced vascular leakage is an integral component of many highly prevalent human diseases, including allergies, asthma, and anaphylaxis. Yet, how histamine induces the disruption of the endothelial barrier is not well defined. By using genetically modified animal models, pharmacologic inhibitors, and a synthetic biology approach, here we show that the small GTPase RhoA mediates histamine-induced vascular leakage. Histamine causes the rapid formation of focal adherens junctions, disrupting the endothelial barrier by acting on H1R Gα(q)-coupled receptors, which is blunted in endothelial Gα(q/11) KO mice. Interfering with RhoA and ROCK function abolishes endothelial permeability, while phospholipase Cβ plays a limited role. Moreover, endothelial-specific RhoA gene deletion prevents vascular leakage and passive cutaneous anaphylaxis in vivo, and ROCK inhibitors protect from lethal systemic anaphylaxis. This study supports a key role for the RhoA signaling circuitry in vascular permeability, thereby identifying novel pharmacological targets for many human diseases characterized by aberrant vascular leakage

The remarkable multivalency of the Hsp70 chaperones

Hsp70 proteins are key to maintaining intracellular protein homeostasis. To carry out this task, they employ a large number of cochaperones and adapter proteins. Here, we review what is known about the interaction between the chaperones and partners, with a strong slant toward structural biology. Hsp70s in general, and Hsc70 (HSPA8) in particular, display an amazing array of interfaces with their protein cofactors. We also review the known interactions between Hsp70s with lipids and with active compounds that may become leads toward Hsp70 modulation for treatment of a variety of diseases