BackgroundPulmonary vascular remodeling of pulmonary arterial hypertension (PAH) is characterized by an inappropriate increase of vascular cells. The receptor for advanced glycation end products (RAGE) is a type I single-pass transmembrane protein belonging to the immunoglobulin superfamily and is involved in a broad range of hyperproliferative diseases. RAGE is also implicated in the etiology of PAH and is overexpressed in pulmonary artery smooth muscle cells (PASMCs) in patients with PAH. We examined the role of RAGE in the inappropriate increase of PASMCs in patients with PAH.Methods and resultsPASMCs were obtained from 12 patients with PAH including 9 patients with idiopathic PAH (IPAH) and 3 patients with heritable PAH (HPAH) (2 patients with BMPR2 mutation and one patient with SMAD9 mutation) who underwent lung transplantation. Western blot analysis and immunofluorescence staining revealed that RAGE and S100A8 and A9, ligands of RAGE, were overexpressed in IPAH and HPAH-PASMCs in the absence of any external growth stimulus. PDGF-BB (10 ng/mL) up-regulated the expression of RAGE in IPAH and HPAH-PASMCs. PAH-PASMCs are hyperplastic in the absence of any external growth stimulus as assessed by 3H-thymidine incorporation. This result indicates overgrowth characterized by continued growth under a condition of no growth stimulation in PAH-PASMCs. PDGF-BB stimulation caused a higher growth rate of PAH-PASMCs than that of non-PAH-PASMCs. AS-1, an inhibitor of TIR domain-mediated RAGE signaling, significantly inhibited overgrowth characterized by continued growth under a condition of no growth stimulation in IPAH and HPAH-PASMCs (P<0.0001). Furthermore, AS-1 significantly inhibited PDGF-stimulated proliferation of IPAH and HPAH-PASMCs (P<0.0001).ConclusionsRAGE plays a crucial role in the inappropriate increase of PAH-PASMCs. Inhibition of RAGE signaling may be a new therapeutic strategy for PAH.

PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment.

Vascular medial calcification is often observed in patients with arteriosclerosis. It is also associated with systolic hypertension, wide pulse pressure, and fluctuation of blood pressure, which results in cardiovascular events. Eicosapentaenoic acid (EPA) has been shown to suppress vascular calcification in previous animal experiments. We investigated the inhibitory effects of EPA on Wnt signaling, which is one of the important signaling pathways involved in vascular calcification. Intake of food containing 5% EPA resulted in upregulation of the mRNA expression of Klotho, an intrinsic inhibitor of Wnt signaling, in the kidneys of wild-type mice. Expression levels of β-catenin, an intracellular signal transducer in the Wnt signaling pathway, were increased in the aortas of Klotho mutant (kl/kl) mice compared to the levels in the aortas of wild-type mice. Wnt3a or BIO, a GSK-3 inhibitor that activates β-catenin signaling, upregulated mRNA levels of AXIN2 and LEF1, Wnt signaling marker genes, and RUNX2 and BMP4, early osteogenic genes, in human aorta smooth muscle cells. EPA suppressed the upregulation of AXIN2 and BMP4. The effect of EPA was cancelled by T0070907, a PPARγ inhibitor. The results suggested that EPA could suppress vascular calcification via the inhibition of Wnt signaling in osteogenic vascular smooth muscle cells via PPARγ activation.

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A 41-year-old man was referred to our hospital for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). On admission, he was in World Health Organization functional class III. Right heart catheterization demonstrated that pulmonary arterial pressure (systolic/diastolic/mean) was 140/42/71 mm Hg, cardiac index was 1.6 L/min/m2 and pulmonary vascular resistance was 1663 dyn ·s·cm -5 . The patient had severe pulmonary hypertension and was considered inoperable because of peripheral organized thrombi and coexisting seminoma; therefore, balloon pulmonary angioplasty (BPA) was performed. After BPA, pulmonary angiography showed improvement of pulmonary arterial flow ( Figure 1A). Pulmonary arterial pressure was 108/42/67 mm Hg and cardiac index was 2.5 L/ min/m 2 when he returned to the cardiac care unit after BPA. His condition temporarily improved; however, 2 hours later, it deteriorated because of reperfusion pulmonary injury and gastrointestinal bleeding. He required mechanical ventilation and percutaneous cardiopulmonary support. To improve hemodynamics, another session of BPA was tried 9 days later (Figures 2A and 3A) and pulmonary arterial pressure seemed to improve to 83/48/58 mm Hg. However, he died from right heart failure on day 26 after BPA despite intensive care.Histological analysis of the autopsy specimens showed recanalized thrombi in the bilateral elastic pulmonary arteries ( Figure 4). Diffuse pulmonary arterial medial and intimal thickening were also observed in muscular pulmonary arteries. These findings are consistent with CTEPH and the diagnosis was confirmed. The arterial media was dissected near the lamina elastica interna by BPA ( Figures 1B, 2B, and 3B). The organized thrombi were forced to one side and the dissection formed pseudovascular spaces that configured new lumina, which were larger than the original channels. Newly formed intima was observed on the inner surface of these pseudovascular spaces ( Figures 1B-c, 2B-b, and 3B-b, black arrowheads).According to the guidelines for the diagnosis and treatment of pulmonary hypertension, pulmonary endarterectomy is a standard therapy for patients with CTEPH with proximal thrombi.1 However, not all patients can undergo this curative surgery because of the presence of thrombi in distal pulmonary arteries, difficulty of the operation, or comorbidities. We have reported that BPA could improve hemodynamics in inoperable patients with CTEPH.2 However, it is unknown how pulmonary arteries are changed by BPA and the mechanism by which hemodynamic improvement is achieved, although thrombi are not removed from the affected arteries. We have recently reported a case in which we were able to examine a pulmonary artery in a single lobe after BPA.3 A pathological examination of the dilated lesion showed that the vascular lumen was dilated by a small incision and compression of the thrombi without dissection. In contrast, the histology of the present case demonstrated that the lumina were dilated by the dissection at a plane in the media (...