The protective effects of PCPA against monocrotaline-induced pulmonary arterial hypertension are mediated through the downregulation of NFAT-1 and NF-κB

Abstract

Inflammation and remodeling play a role in the pathogenesis of pulmonary arterial hypertension (PAH). Nuclear factor-κB (NF-κB) and nuclear factor of activated T cells-1 (NFAT-1) participate in inflammation and remodeling in a number of diseases. As a tryptophan hydroxylase inhibitor, 4-chloro-DL-phenylalanine (PCPA) had been reported to exert anti-inflammatory and remodeling effects. Therefore, we hypothesized that PCPA may attenuate monocrotaline (MCT)-induced PAH through the NFAT-1 and NF-κB signaling pathways. In order to confirm our hypothesis, we divided 68 Sprague-Dawley male rats into 4 groups as follows: the control, MCT, MCT + P1 and MCT + P2 groups. MCT was administered at a dose of 60 mg/kg once via intraperitoneal injection. PCPA was administered via intraperitoneal injection at a dose of 50 or 100 mg/kg once daily for 21 consecutive days. We then measured the hemodynamic index and morphological analysis was carried out on the lung tissues. Western blot analysis and immunohistochemistry were used to examine the levels of NFAT-1 and NF-κB p-65. The expression levels of phosphorylated inhibitor of NF-κB kinase (p-IKK), IKK, phosphorylated extracellular signal-regulated kinase (p-ERK), ERK, intercellular adhesion molecule-1 (ICAM-1) and interleukin-6 (IL-6) were examined by western blot analysis. MCT was found to significantly induce PAH, with inflammation and remodeling of the lung tissues. This was associatd with an increased expression of NFAT-1, p-IKK, p-ERK and nuclear p65. PCPA significantly attenuated MCT-induced inflammation and arterial remodeling, and decreased the expression of NFAT-1, as well as that of relevant proteins of the NF-κB signaling pathway. The above-mentioned findings suggest that the inhibitory effects of PCPA on MCT-induced inflammation and arterial remodeling are related to the downregulation of the NFAT-1 and NF-κB signaling pathways in rats with PAH.

Epigenetic Regulation of Endothelial Dysfunction and Inflammation in Pulmonary Arterial Hypertension

“…The canonical NF-κB pathway requires nuclear translocation of a p65/p50 dimer to the nucleus, leading to activation of gene transcription [136]. Activation of this pathway is a key player in vascular and cardiac remodeling, including in PAH and experimental models of severe PH, as shown by our group [94, [137][138][139][140][141][142][143]. Our group has also shown that inhibition of NF-κB reduces occlusive pulmonary arteriopathy in severe PH in rats [141].…”

Inhibitory effects of formononetin on the monocrotaline‑induced pulmonary arterial hypertension in rats

“…The precise action mechanism that leads to PaH remains to be elucidated, but previous studies have indicated that erK and nF-κB signals are closely related to the pathogenesis of PaH (42,43). erK is a main factor of the MaPK family, and its activity in animals with PaH is enhanced (43).…”

“…in addition, p-erK is increased in rat lungs exposed to McT, and the suppression of p-erK can prevent the pulmonary vascular remodeling associated with PaH formation (44). notably, erK signaling has been demonstrated to coordinate ecM deposition and inflammatory responses (42,44). The results of the present study were consistent with these previous studies, demonstrating that p-erK was distinctly elevated in the rat lungs exposed to McT, and FMn administration markedly decreased the activated erK induced by McT.…”

PCPA protects against monocrotaline-induced pulmonary arterial remodeling in rats: potential roles of connective tissue growth factor

“…injection of MCT induces vascular remodeling, increases PASMC proliferation and decreases apoptosis by up-regulating anti-apoptotic proteins [ 31 , 32 ]. PCPA, as an inhibitor of 5-HT synthesis, has amelioration effect on remodeling in the PAH [ 31 , 33 ]. But whether PCPA can regulate the apoptosis and its associated signaling pathway is unknown.…”

“…Serotonin plays an important role in PAH. Results from our laboratories showed that the rate-limiting enzyme of serotonin synthesis, TPH1 and SERT expression is increased in PAH [ 31 , 33 ]. Serotonin mediates PAH by inducing pulmonary vascular remodeling and vasoconstriction [ 27 ].…”