Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that hypoxia-inducible factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This Review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell-specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.

/pdf/hypoxia-inducible-factor-signaling-in-pulmonary-hypertension-2c8twwtv1d.pdf

Hypoxia-inducible factor signaling in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a rare, complex, and progressive disease that is characterized by the abnormal remodeling of the pulmonary arteries that leads to right ventricular failure and death. Although our understanding of the causes for abnormal vascular remodeling in PAH is limited, accumulating evidence indicates that endothelial cell (EC) dysfunction is one of the first triggers initiating this process. EC dysfunction leads to the activation of several cellular signalling pathways in the endothelium, resulting in the uncontrolled proliferation of ECs, pulmonary artery smooth muscle cells, and fibroblasts, and eventually leads to vascular remodelling and the occlusion of the pulmonary blood vessels. Other factors that are related to EC dysfunction in PAH are an increase in endothelial to mesenchymal transition, inflammation, apoptosis, and thrombus formation. In this review, we outline the latest advances on the role of EC dysfunction in PAH and other forms of pulmonary hypertension. We also elaborate on the molecular signals that orchestrate EC dysfunction in PAH. Understanding the role and mechanisms of EC dysfunction will unravel the therapeutic potential of targeting this process in PAH.

https://www.mdpi.com/2227-9059/9/1/57/pdf

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

A cotton NAC transcription factor GhirNAC2 plays positive roles in drought tolerance via regulating ABA biosynthesis

Pathological mechanisms of pulmonary arterial hypertension (PAH) remain largely unexplored. Effective treatment of PAH remains a challenge. The aim of this study was to discover the underlying mechanism of PAH through functional metabolomics and to help develop new strategies for prevention and treatment of PAH.Metabolomic profiling of plasma in patients with idiopathic PAH was evaluated through high-performance liquid chromatography mass spectrometry, with spermine identified to be the most significant and validated in another independent cohort. The roles of spermine and spermine synthase were examined in pulmonary arterial smooth muscle cells (PASMCs) and rodent models of pulmonary hypertension.Using targeted metabolomics, plasma spermine levels were found to be higher in patients with idiopathic PAH compared to healthy controls. Spermine administration promoted proliferation and migration of PASMCs and exacerbated vascular remodelling in rodent models of pulmonary hypertension. The spermine-mediated deteriorative effect can be attributed to a corresponding upregulation of its synthase in the pathological process. Inhibition of spermine synthase in vitro suppressed platelet-derived growth factor-BB-mediated proliferation of PASMCs, and in vivo attenuated monocrotaline-mediated pulmonary hypertension in rats.Plasma spermine promotes pulmonary vascular remodelling. Inhibiting spermine synthesis could be a therapeutic strategy for PAH.

Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial 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. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1β]), which is shared by HIF-1α and AhR. Su reduced HIF-1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.

/pdf/role-of-the-aryl-hydrocarbon-receptor-in-sugen-5416-induced-8hikvog8ut.pdf

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

Cowpea (Vigna unguiculata L.) is one of the most important grain legume supplying necessarily dietary proteins. Although its can tolerate drought environment, still the severe condition can limit the growth and development of this plant. Abscisic acid (ABA) has a crucial function in stress physiology, but little information is available for methods describing ABA determination in cowpea and its relationship to drought stress based on cowpea varieties with different capability of drought resistance. Here, an effectual approach based on high-performance liquid chromatography (HPLC) method was established to separate and determine the endogenous abscisic acid in cowpea and further the cowpea varieties with different capability of drought resistance were used to explore relationships between ABA content and drought stress. The results potentially provided useful reference for the cultivation of cowpea crop. Results-This method showed good liner regression (R2 = 0.9998), coupled with high stability, precision and repeatability. The endogenous ABA decreased under drought treatment and the drought sensitive line had higher ABA content than drought resistant one, suggesting ABA performs a vital function in cowpea’s response and resistance to drought stress. The studies potentially provided useful reference for the cultivation and breeding of cowpea crop.

/pdf/determination-of-abscisic-acid-and-its-relationship-to-48nae4x74v.pdf

Determination of Abscisic Acid and its Relationship to Drought Stress Based on Cowpea Varieties with Different Capability of Drought Resistance

Coronary artery disease (CAD) and pulmonary arterial hypertension (PAH) are two of the most dangerous vascular diseases. Their etiology and pathogenesis are not yet fully understood, thus it remains difficult to achive great advance in the diagnose, therapy and prognosis techniques. microRNAs (miRNAs), a class of highly conserved, small, noncoding RNAs, critically mediate the post-transcriptional gene modulation, which regulates an array of important physiopathological processes including those occurring in cardiac and pulmonary systems. Thereby manipulation of miRNA expression could potentially be applied therapeutically. In this review, we summarize the current knowledge on the roles of miRNAs in the development of vascular diseases, especially in CAD and PAH, providing a theoretical basis for potential uses of miRNA in diagnosis, prognosis, and therapy in these cardiovascular diseases.

Roles of microRNA in vascular diseases in cardiac and pulmonary systems.

The gene sequences of 4-coumarate:coenzyme A ligase (4CL) family of Scutellaria baicalensis came from the GenBank Database. With help of some bioinformatics tools such as Vector NTI Suite 8, ProtParam and SWISS-MODEL and so on, a series of biological information of their nucleic acid sequences and amino acid sequences were predicted and analyzed and the results were revealed as following: Two 4cl member genes share high similarity in structure and properties on level of nucleic acid and amino acid molecular. 4CLs are hydrophic proteins without any transmembrane topological structure and some crucial motifs were found. The secondary structures of Sb4CLs are mainly composed of random coil and α-helix and the models of their tertiary structures were built. In silico analysis of Sv4CL was finished, which would pave for further studies of physichemical properties of 4CL family and its related molecular mechanism of flavonoid metabolic regulation.

In silico Analysis of 4CL Family in Scutellaria baicalensis through Biocomputational Tools and Servers

Pulmonary arterial hypertension (PAH) is characterized by endothelial dysfunction and structural remodeling of the pulmonary vasculature, mediated initially by reduced oxygen availability in the lungs. Hypoxia inducible factor (HIF), consisting of the functional subunit, HIF‑1α, and the constitutively expressed HIF‑1β, is involved in the pathological processes associated with hypoxia. In the current study, the sequences of cDNAs and amino acids of HIF were characterized and analyzed using online bioinformatics tools. To further evaluate whether HIF accounts for the occurrence of PAH, the present study determine the expression and phosphorylation levels of HIF and its associated pathways, including extracellular signal‑regulated kinase (Erk)1/2 and phosphoinositide 3‑kinase (PI3K)/Akt, in the lungs of patients with PAH by reverse transcription‑quantitative polymerase chain reaction and western blotting. The mRNA expression levels of PI3K, Erk2, and HIF‑1α in the patients with PAH were significantly higher, compared with those in the control group, by 3.6‑fold (P 0.05). The protein levels of phosphorylated (p‑)Akt, Erk1/2, p‑Erk1/2, HIF‑1α and HIF‑1β were significantly increased by 5.89‑, 0.5‑, 0.59‑, 1.46‑ and 0.92‑fold, respectively, in the patients with PAH, compared with those in the controls group (P<0.01 for p‑Akt, Erk1/2; P<0.05 for p‑Erk1/2, HIF‑1α and HIF‑1β). These findings suggested that the mitogen‑activated protein kinase and PI3K/Akt signaling pathways, and HIF‑1 may perform a specific function in the pathogenesis of PAH.

/pdf/expression-and-analyses-of-the-hif-1-pathway-in-the-lungs-of-hvkeep8orv.pdf

Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension

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Determination of Abscisic Acid and its Relationship to Drought Stress Based on Cowpea Varieties with Different Capability of Drought Resistance

Roles of microRNA in vascular diseases in cardiac and pulmonary systems.

In silico Analysis of 4CL Family in Scutellaria baicalensis through Biocomputational Tools and Servers

Expression and analyses of the HIF-1 pathway in the lungs of humans with pulmonary arterial hypertension