We have previously demonstrated that low-dose lipopolysaccharide (LPS) is a potent stimulus for the development of PAH in the context of a genetic PAH mouse model of BMPR2 dysfunction.
Pulmonary arterial hypertension is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and is increasingly recognized as a systemic disease.
Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial endothelial cell (PAEC) dysfunction and apoptosis, pulmonary arterial smooth muscle cell (PASMC) proliferation, inflammation, vasoconstriction, and metabolic disturbances that include disrupted bone morphogenetic protein receptor (BMPR2)-peroxisome proliferator-activated receptor gamma (PPARγ) axis and DNA damage.
Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.
Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH.
In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others.
Among them, caveolin-1, filamin A expression, and cathepsin D combined with macrophagocytes counts were significantly increased; glutathione S-transferase mu1 (GSTM1) expression was significantly decreased in the irreversible CHD-PAH group (all P < 0.05).
Even in the absence of BMPR2 mutations, increased transforming growth factor (TGF)β receptor signalling and decreased BMPRII signalling have been shown to contribute to PAH pathogenesis.
Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH.
Conclusions- EC Cav-1 depletion occurs, in part, via Cav-1+ extracellular vesicle shedding into the circulation, which contributes to increased TGF-β signaling, EC proliferation, vascular remodeling, and pulmonary arterial hypertension.
The present study aimed to characterize the functional properties and regulation of wild-type (WT) and mutated TASK-1 channels and determine how these might contribute to PAH and its treatment.
Treatment with BMPR2-BM-ELPC attenuated PAH as demonstrated by a reduction in right ventricular hypertrophy as well as right ventricular systolic and mean pulmonary arterial pressures.
We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH).
Arterial remodeling-a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH)-is regulated by TGFβ1 (transforming growth factor-β1)-TGFβ receptors and the antagonistic, vasoprotective BMPR2 (bone morphogenetic protein receptor 2)-PPARγ (peroxisome proliferator-activated receptor-γ) axis.
Here we show that the receptor BMP type 2 (BMPR2) serves as a central gatekeeper of this balance, highlighted by its deregulation in diseases such as pulmonary arterial hypertension (PAH).
Loss of function mutations in the type II BMP receptor BMPR2 are the leading cause of pulmonary arterial hypertension (PAH), a rare disease of vascular occlusion that leads to high blood pressure in the pulmonary arteries.
R899X<sup>+/-</sup> BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection.
This study aimed to investigate the effect of a mutated caveolin-1 (Cav1<sup>F92A</sup>) gene from bone marrow mesenchymal stem cells (rBMSCs) on phenotypic switching in the smooth muscle cells during PAH.