Mixed Lineage Kinase 3 Regulates Blood Pressure Through Kinase Independent Effects in the Vasculature

Background Many anti-remodeling signaling molecules also modulate blood pressure. Thus, therapeutic modulation of these potential therapeutic targets has been limited by hypotension. Mixed lineage kinase 3 (MLK3) opposes pathologic cardiac remodeling, but its role in blood pressure (BP) has not been studied. MLK3 activates JNK signaling through kinase dependent effects, and opposes RhoA activation through kinase-independent mechanisms, but the relevance of these mechanisms to BP is unknown. We investigated the effect of genetic deletion of MLK3 on BP. Methods and Results Using ambulatory telemetric monitoring in 3 month old male mice, MLK3 -/- mice had significant hypertension compared to wild type (WT) littermates (WT systolic BP 121 ± 2 mmHg, MLK3-/- 162 ± 5 mmHg; n=3; p Conclusions These data demonstrate that MLK3 deletion leads to hypertension with increased arterial stiffness, reduced distensibility and eutrophic remodeling of resistance vessels, but retained BP responsiveness to downstream ROCK inhibition. Together with previous work, these findings support that MLK3 modulates cardiac remodeling through a kinase dependent mechanism while modulating blood pressure through kinase-independent effects. Because hypotension limits many heart failure therapies, delineating vascular versus cardiac mechanisms of MLK3 signaling has the potential to suggest novel approaches to heart failure treatment.