Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype.

Unlabelled: The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke.

An Inducible and Vascular Smooth Muscle Cell-Specific Pink1 Knockout Induces Mitochondrial Energetic Dysfunction during Atherogenesis.

DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its effect on VSMC-dependent atherogenesis and VSMC energetic metabolism .

Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat.

The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia.

Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α.

Background Women are at greater risk of developing pulmonary arterial hypertension, with estrogen and its downstream metabolites playing a potential role in the pathogenesis of the disease. Hypoxia-inducible factor-1-α (HIF 1α) is a pro-proliferative mediator and may be involved in the development of human pulmonary arterial hypertension . The estrogen metabolite 2-methoxyestradiol (2 ME 2) has antiproliferative properties and is also an inhibitor of HIF 1α.

The Role of Sex in the Pathophysiology of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II).

Impaired mitochondrial respiration in human carotid plaque atherosclerosis: A potential role for Pink1 in vascular smooth muscle cell energetics.

Background And Aims: DNA damage and mitochondrial dysfunction are thought to play an essential role in ageing and the energetic decline of vascular smooth muscle cells (VSMCs) essential for maintaining plaque integrity. We aimed to better understand VSMCs and identify potentially useful compensatory pathways that could extend their lifespan. Moreover, we wanted to assess if defects in mitochondrial respiration exist in human atherosclerotic plaques and to identify the appropriate markers that may reflect a switch in VSMC energy metabolism.

Role of the Aryl Hydrocarbon Receptor in Sugen 5416-induced Experimental Pulmonary Hypertension.

Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH.

Lin28A induces energetic switching to glycolytic metabolism in human embryonic kidney cells.

Background: Loss of a cell's capacity to generate sufficient energy for cellular functions is a key hallmark of the ageing process and ultimately leads to a variety of important age-related pathologies such as cancer, Parkinson's disease and atherosclerosis. Regenerative medicine has sought to reverse these pathologies by reprogramming somatic cells to a more juvenile energetic state using a variety of stem cell factors. One of these factors, Lin28, is considered a candidate for modification in the reprogramming of cellular energetics to ameliorate the ageing process while retaining cell phenotype.

Sex affects bone morphogenetic protein type II receptor signaling in pulmonary artery smooth muscle cells.

Rationale: Major pulmonary arterial hypertension (PAH) registries report a greater incidence of PAH in women; mutations in the bone morphogenic protein type II receptor (BMPR-II) occur in approximately 80% of patients with heritable PAH (hPAH).

Objectives: We addressed the hypothesis that women may be predisposed to PAH due to normally reduced basal BMPR-II signaling in human pulmonary artery smooth muscle cells (hPASMCs).

Methods: We examined the BMPR-II signaling pathway in hPASMCs derived from men and women with no underlying cardiovascular disease (non-PAH hPASMCs).