In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
Abstract:
Background: 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 〈 0.05). The MLK3 kinase inhibitor URMC-099 (10 mg/kg IP) did not affect BP in WT mice. By contrast, inhibition of downstream RhoA dependent Kinase (ROCK) with Y-27632 (15 mg/kg) fully normalized BP in MLK3 -/- mice (SBP WT baseline 126 ± 2 mmHg; WT ROCK inhibitor 94 ± 2 mmHg; MLK-/- baseline 163 ±6 mmHg; MLK3 -/- ROCK inhibitor 94 ± 12 mmHg; n=5 WT, 9 MLK3-/-). Aortic pulse wave velocity was elevated in MLK-/- mice (2.7 ± 0.1 mm/ms WT vs 3.6 ± 0.2 mm/ms MLK3-/-; p 〈 0.05) indicating increased aortic stiffness. Pressure myography in mesenteric resistance arterioles of MLK3 -/- mice revealed reduced distensibility compared to WT. Both pressure myography and direct histological measurement in resistance arterioles demonstrated reduced passive luminal diameter but preserved wall cross sectional area in MLK3-/- arterioles, indicating eutrophic remodeling. Compared with dispersed aortic smooth muscle cells from WT littermates, MLK3 -/- cells had increased actin stress fiber accumulation and cell area. Summary and 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.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/res.125.suppl_1.625
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2019
detail.hit.zdb_id:
1467838-X
