Angiotensin‑converting enzyme 2 alleviates pulmonary artery hypertension through inhibition of focal adhesion kinase expression

Abstract

Focal adhesion kinase (FAK) is an important therapeutic target in pulmonary artery hypertension (PAH); however, the mechanism of its activation remains unknown. The present study aimed to investigate whether angiotensin-converting enzyme 2 (ACE2) could regulate FAK and alleviate PAH in a rat model of PAH established with a single administration of monocrotaline followed by continuous hypoxia treatment. In the current study, right ventricular pressure, body weight and the right ventricular hypertrophy index were measured, and hematoxylin-eosin staining was performed on lung tissues to determine whether the modeling was successful. Changes in the serum levels of FAK were measured using an ELISA kit to evaluate the association between ACE2 and FAK. The mRNA expression levels of ACE2, FAK, caspase-3 and survivin were determined using reverse transcription-quantitative PCR (RT-qPCR). The protein expression levels of ACE2, phosphorylated FAK/FAK, cleaved caspase-3/pro-caspase-3 and survivin were determined via western blotting. Immunohistochemistry was applied to detect the expression of FAK around the pulmonary arterioles. Apoptosis of smooth muscle cells around pulmonary arterioles was observed by TUNEL staining. After treatment with the ACE2 activator DIZE or inhibitor DX-600, the results demonstrated that ACE2 reduced PAH-induced changes in arteriole morphology compared with the control. It also inhibited FAK expression in serum. WB and RT-qPCR results suggested that ACE2 inhibited the expression of FAK and pathway-related proteins, and promoted caspase-3 expression. Additionally, ACE2 reduced FAK expression around the pulmonary arterioles and promoted smooth muscle cell apoptosis. The results indicated that ACE2 activation inhibited FAK expression, leading to alleviation of the symptoms of PAH.

Identifying potential ferroptosis-related biomarkers and therapeutic targets for Idiopathic Pulmonary Hypertension in the context of predictive, preventive, and personalized medicine by integrative bioinformatics approaches

“…The GO enrichment analysis highlighted signi cant associations of DE-FRGs with CC ("focal adhesion," "cell-substrate junction," "membrane raft"), BP ("cellular response to chemical stress," "cellular response to peptidyl-serine phosphorylation," "peptidyl-serine modi cation"), and MF ("RNA polymerase II-speci c DNA-binding transcription factor binding," "DNA-binding transcription factor binding," "phosphoprotein binding"). Notably, focal adhesion, which is critical for cell adhesion and migration within the matrix, may regulate interactions between pulmonary vascular endothelial cells and their environment during remodeling [37] .…”

Renal Abscess Caused by Crizotinib: A Rare Case Report

“…Based on the above analysis, we realize that the incidence of renal cyst as a complication in patients with hypertension taking crizotinib may be different from that in patients without hypertension. Furthermore, one study showed that angiotensin-converting enzyme 2 inhibits FAK expression ( 20 ). FAK has been described above to have an important role in the development of renal cysts; thus, we suspected that the incidence of renal cyst as a complication in patients with hypertension being treated with angiotensin-converting enzyme inhibitors and who are taking crizotinib is higher than that in patients without angiotensin-converting enzyme inhibitor treatment.…”

SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension

“…Similar to normoxic conditions, SPARC silencing (1) decreased proproliferative (MKI67, CCND1, PCNA expression, and AKT phosphorylation; Figure 5A, 5B, 5G, and 5H) and apoptosis inhibitory (BCL2, BCL6) signaling (Figure 5A and 5G), as well as proliferation (Figure 5C and 5E), whereas (2) proapoptotic signaling (BAX; Figure 5B and To determine further possible regulators of PASMCs proliferation and apoptosis, we focused on signaling pathways connected to SPARC signaling [11][12][13] and, in addition, are known to contribute to vascular cell dysregulation in PH. [14][15][16] SPARC silencing in PASMCs consistently reduced ERK1/2 (extracellular signal-regulated kinase) mitogen-activated protein (MAP) kinase phosphorylation under both normoxic and hypoxic conditions. The integrin-binding protein FAK (focal adhesion kinase) phosphorylation, a possible regulator of AKT phosphorylation, was reduced by SPARC silencing only under hypoxic conditions, whereas the phosphorylation of P38 (mitogenactivated protein kinase 14) and the mTOR (mammalian target of rapamycin) downstream target P70S6K (ribosomal protein S6 kinase) was affected by SPARC silencing in normoxic conditions only (Figure S8A and S8B).…”