Endothelium-specific SIRT7 targeting ameliorates pulmonary hypertension through Krüpple-like factor 4 deacetylation

Abstract

Aims Pulmonary hypertension (PH) is a pulmonary vascular disease characterized by a high mortality rate. Pulmonary arterial endothelium cells (PAECs) serve as a primary sensor of various environmental cues, such as shear stress and hypoxia, but PAEC dysfunction may trigger vascular remodeling during the onset of PH. This study was aimed to illustrate the role of SIRT7 in endothelial dysfunction during PH, and explore the potential therapeutic strategy for PH. Methods and Results SIRT7 levels were measured in human and murine experimental PH samples. Bioinformatic analysis, immunoprecipitation, and deacetylation assay was used to identify the association between SIRT7 and Krüpple-like factor 4 (KLF4), a key transcription factor essential for EC homeostasis. Sugen5416+hypoxia (SuHx)-induced PH mouse models and cell cultures were used for the study of the therapeutic effect of SIRT7 for PH. SIRT7 level was significantly reduced in lung tissues and PAECs from PH patients and the SuHx-induced PH mouse model as compared with healthy controls. Pulmonary endothelium-specific depletion of Sirt7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy in the SuHx-induced PH model. At the molecular level, we identified KLF4 as a downstream target of SIRT7, which deacetylated KLF4 at K228 and inhibited the ubiquitination-proteasome degradation. Thus, the SIRT7/KLF4 axis maintained PAEC homeostasis by regulating proliferation, migration, and tube formation. PAEC dysfunction was reversed by adeno-associated virus type 1 vector mediated endothelial overexpression of Sirt7 or supplementation with NAD+ intermediate nicotinamide riboside which activated Sirt7; both approaches successfully reversed PH phenotypes. Conclusions The SIRT7/KLF4 axis ensures PAEC homeostasis, and pulmonary endothelium-specific SIRT7 targeting might constitute a PH therapeutic strategy. Translational Perspective Pulmonary endothelial cell dysfunction is pivotal in vascular remodeling process during pulmonary hypertension pathogenesis. We identified a SIRT7/KLF4 axis essential for pulmonary endothelial homeostasis, however compromised in pulmonary hypertension patients and animal models. Pulmonary endothelium-specific Sirt7 gene delivery or treatment with NAD+ precursor reversed PH phenotypes, providing a new therapeutic strategy for PH.

MiR-148a-3p/SIRT7 Axis Relieves Inflammatory-Induced Endothelial Dysfunction

“…Indeed, SIRT7 loss during LPS exposure has been associated with inflammation and fibrosis in murine lung tissues in vivo, while SIRT7 silencing suppressed LPS-induced pro-inflammatory responses and NF-κB signaling, by modulating the TGF-β pathway, in primary pulmonary endothelial cells [35]. The pulmonary endothelium-specific depletion of SIRT7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy [32]. Moreover, in pulmonary arterial endothelium cells, the overexpression of SIRT7 reversed EC dysfunction occurring under pulmonary hypertension by deacetylating and stabilizing KLF4 [32].…”

“…The pulmonary endothelium-specific depletion of SIRT7 increased right ventricular systolic pressure and exacerbated right ventricular hypertrophy [32]. Moreover, in pulmonary arterial endothelium cells, the overexpression of SIRT7 reversed EC dysfunction occurring under pulmonary hypertension by deacetylating and stabilizing KLF4 [32]. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuates inflammation, induces endomesenchymal transition, and increases vascular permeability [35].…”

“…SIRT7 overexpression reverted endothelial dysfunction and maintained cell homeostasis by regulating proliferation, migration, and tube formation in pulmonary arterial endothelium cells [32] and exerted a rescue effect against oxidative stress-induced HU-VECs [33]. In response to inflammatory stimuli, SIRT7 promoted the activation of NF-κB signaling via Toll-like receptor 2, while its decay prevented the development of chronic inflammatory disorder [34].…”