Far‐infrared radiation alleviates cisplatin‐induced vascular damage and impaired circulation via activation of HIF‐1α

Abstract

Severe vascular damage and complications are often observed in cancer patients during treatment with chemotherapeutic drugs such as cisplatin. Thus, development of potential options to ameliorate the vascular side effects is urgently needed. In this study, the effects and the underlying mechanisms of far-infrared radiation (FIR) on cisplatin-induced vascular injury and endothelial cytotoxicity/dysfunction in mice and human umbilical vein endothelial cells (HUVECs) were investigated. An important finding is that the severe vascular stenosis and poor blood flow seen in cisplatintreated mice were greatly mitigated by FIR irradiation (30 minutes/day) for 1-3 days.Moreover, FIR markedly increased the levels of phosphorylation of PI3K and Akt, and VEGF secretion, as well as the expression and the activity of hypoxia-inducible factor 1α (HIF-1α) in cisplatin-treated HUVECs in a promyelocytic leukemia zinc finger protein (PLZF)-dependent manner. However, FIR-stimulated endothelial angiogenesis and VEGF release were significantly diminished by transfection with HIF-1α siRNA.We also confirmed that HIF-1α, PI3K, and PLZF contribute to the inhibitory effect of FIR on cisplatin-induced apoptosis in HUVECs. Notably, FIR did not affect the anticancer activity and the HIF-1α/VEGF cascade in cisplatin-treated cancer cells under normoxic or hypoxic condition, indicating that the actions of FIR may specifically target endothelial cells. It is the first study to demonstrate that FIR effectively attenuates cisplatin-induced vascular damage and impaired angiogenesis through activation of HIF-1α-dependent processes via regulation of PLZF and PI3K/Akt. Taken together, cotreatment with the noninvasive and easily performed FIR has a therapeutic potential to prevent the pathogenesis of vascular complications in cancer patients during cisplatin treatment.

Cisplatin causes erectile dysfunction by decreasing endothelial and smooth muscle content and inducing cavernosal nerve senescence in rats

“…In our results, CD31 staining and eNOS levels in the corpus cavernosum were decreased after CDDP treatment. CDDP can induce apoptosis in HUVECs ( 30 ). Furthermore, CDDP also upregulates NF-κB/ICAM-1 to affect the production of nitric oxide (NO) and cGMP, which leads to endothelial dysfunction ( 31 ).…”

An integrative review of nonobvious puzzles of cellular and molecular cardiooncology

“…Moreover, CIS upregulates hypoxia-inducible factor-1α (HIF-1α), which positively regulates angiogenesis-related genes at the transcriptional level [ 279 ], although the production of VEGF remained unchanged. Instead, CIS intensified the interaction of HIF-1α with p53 indicating that this transcription factor may act as a switch directing cells toward p53-dependent apoptosis rather than as a regulator of EC survival and angiogenesis [ 280 ]. CIS-treated apoptotic ECs were characterized in vitro by a morphological depopulation, as evidenced according to decreased transendothelial electrical resistance and repressed expression of tight junction proteins, occludin and zonula occludens-2 (ZO-2) [ 281 ].…”

“…It must be stressed, however, that literature data regarding the modulation of angiogenesis by platins concern tumor vasculature to the most considerable extent; thus, they are basically uncoupled with potential cardio- and vasotoxicity. CIS inhibits dose-dependent proliferation and tube formation in HUVECs in vitro, as well as rabbit corneal neovascularization in vivo [ 280 , 283 ]. Furthermore, the drug inhibits HUVEC migration and upregulates the activation of p38 MAPK and JNK signaling routes.…”