PDE4B abrogation extenuates angiotensin II-induced endothelial dysfunction related to hypertension through up-regulation of AMPK/Sirt1/Nrf2/ARE signaling.

Endothelial dysfunction is commonly perceived as a precursor in the process of hypertension, a severe cardiovascular disorder. Phosphodiesterase 4B (PDE4B) inactivation has been proposed to exert cardioprotective effects and prevent pulmonary hypertension. However, the role of PDE4B in endothelial dysfunction in hypertension remains inexplicit, which will be investigated in the present work. In angiotensin II (Ang II)-induced human umbilical vein endothelial cells (HUVECs), RT-qPCR and Western blotting were used to analyze PDE4B expression. CCK-8 method was used to detect cell viability. Flow cytometry assay and Caspase 3 assay kit were used to detect cellular apoptotic level. Wound healing and tube formation assays were respectively used to detect cell migration and angiogenesis. Western blotting and corresponding assay kits were respectively used to analyze the expressions and contents of endothelial dysfunction markers. JC-1 assay, RT-qPCR and relevant assay kit were respectively used to detect mitochondrial membrane potential (ΔΨm), quantify mitochondrial DNA (mtDNA) copy number and mitochondrial permeability transition pore (mPTP) opening. Besides, Western blotting was used to analyze the expressions of endoplasmic reticulum stress (ERS) and AMP-activated protein kinase (AMPK)/sirtuin 1 (Sirt1)/nuclear factor-erythroid 2 related factor 2 (Nrf2)/antioxidant response element (ARE) signaling-associated proteins. PDE4B expression was increased in Ang II- induced HUVECs. PDE4B knockdown promoted the viability, migration, angiogenesis while inhibiting the apoptosis, endothelial dysfunction, ERS and mitochondrial damage in Ang II-induced HUVECs. Additionally, PDE4B silence activated AMPK/Sirt1/Nrf2/ARE pathway and AMPK inhibitor Compound C (CC) partially reversed the effects of PDE4B down-regulation on Ang II-induced HUVECs. Conclusively, PDE4B inhibition might protect against Ang II-induced endothelial dysfunction in HUVECs via up-regulating AMPK/Sirt1/Nrf2/ARE pathway, which might be mediated by the suppression of ERS and mitochondrial damage.
Competing Interests: Declaration of Competing Interest None.
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