Dataset Information

LIMK (LIM Kinase) Inhibition Prevents Vasoconstriction- and Hypertension-Induced Arterial Stiffening and Remodeling.

ABSTRACT: Increased arterial stiffness and vascular remodeling precede and are consequences of hypertension. They also contribute to the development and progression of life-threatening cardiovascular diseases. Yet, there are currently no agents specifically aimed at preventing or treating arterial stiffening and remodeling. Previous research indicates that vascular smooth muscle actin polymerization participates in the initial stages of arterial stiffening and remodeling and that LIMK (LIM kinase) promotes F-actin formation and stabilization via cofilin phosphorylation and consequent inactivation. Herein, we hypothesize that LIMK inhibition is able to prevent vasoconstriction- and hypertension-associated arterial stiffening and inward remodeling. We found that small visceral arteries isolated from hypertensive subjects are stiffer and have greater cofilin phosphorylation than those from nonhypertensives. We also show that LIMK inhibition prevents arterial stiffening and inward remodeling in isolated human small visceral arteries exposed to prolonged vasoconstriction. Using cultured vascular smooth muscle cells, we determined that LIMK inhibition prevents vasoconstrictor agonists from increasing cofilin phosphorylation, F-actin volume, and cell cortex stiffness. We further show that localized LIMK inhibition prevents arteriolar inward remodeling in hypertensive mice. This indicates that hypertension is associated with increased vascular smooth muscle cofilin phosphorylation, cytoskeletal stress fiber formation, and heightened arterial stiffness. Our data further suggest that pharmacological inhibition of LIMK prevents vasoconstriction-induced arterial stiffening, in part, via reductions in vascular smooth muscle F-actin content and cellular stiffness. Accordingly, LIMK inhibition should represent a promising therapeutic means to stop the progression of arterial stiffening and remodeling in hypertension.

SUBMITTER: Morales-Quinones M

PROVIDER: S-EPMC7347448 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe cardioprotective properties of sevoflurane have been reported in studies of the left ventricle. However, whether this volatile anesthetic would also be beneficial for pulmonary vascular remodeling and associated right ventricular hypertrophy (RVH) remained to be explored. Here, we investigated the potential benefit of sevoflurane to right heart function in experimental pulmonary arterial hypertension (PAH).MethodsAdult Wistar rats received one dose peritoneal injection of monocrotaline (MCT, 60 mg/kg) or the equal volume of normal saline. Two weeks later, rats were treated with sevoflurane or sham exposure. PAH status and cardiac function were assessed by echocardiography weekly, and the body weight (BW) was monitored every week. After 6 weeks of exercise, Fulton's index calculation, histological observation, IL-6 and TNF-α immunohistochemical analyses, evaluation of MDA, SOD and GSH-Px levels and NF-κB and MAPK active determination were performed in lung and RV tissue samples.ResultsMCT induced pulmonary vascular remodeling, RVH, increased Fulton's index (P<0.01), and right ventricular failure (RVF) in rats. Animals inhaled sevoflurane had an increased cardiac output (P<0.05) and lower incidence of RVF (P<0.05). Also, these animals had a reduced RVEDD, RVWTd and PAID (P<0.05), increased PV (P<0.05), reduced wall thickness and vascular wall area of pulmonary small vascular (vascular external diameter 50-150 um) (P<0.01), reduced RV fibrosis, and increased RV cardiomyocyte area (P<0.01). Furthermore, sevoflurane reduced IL-6 and TNF-α expression in lungs and heart (P<0.01), decreased level of MDA (P<0.01) and increased activity of SOD and GSH-Px (P<0.01). In addition, it decreased the activities of NF-κB and MAPK pathways (P<0.01).ConclusionSevoflurane reduces pulmonary vascular remodeling and RVH in PAH induced by MCT in rats. This effect is likely due to down-regulation of inflammatory factors IL-6 and TNF-α, reduced level of oxidative stress and the inhibition of NF-κB and MAPK pathways.

Dataset Information

LIMK (LIM Kinase) Inhibition Prevents Vasoconstriction- and Hypertension-Induced Arterial Stiffening and Remodeling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets