Key result
Smooth muscle-targeted DLGAP5 knockdown reduces pulmonary pressures and vascular remodeling in experimental pulmonary hypertension.
Why the study?
Pulmonary arterial hypertension manifests through pulmonary vascular remodeling driven by hyper-proliferation and apoptosis resistance of resident pulmonary artery cells, and the role and mechanisms of action of the mitotic spindle-associated microtubule regulator DLGAP5 in this remodeling needed to be determined.
Does smooth muscle-specific knockdown of DLGAP5 attenuate pulmonary vascular cell proliferation, vascular remodeling, and pulmonary hypertension in human PAH cells and mice with SuHx-induced pulmonary hypertension?
Does smooth muscle-specific knockdown of DLGAP5 attenuate pulmonary vascular cell proliferation, vascular remodeling, and pulmonary hypertension in human PAH cells and mice with SuHx-induced pulmonary hypertension?
This study identifies the mitotic regulator DLGAP5 and its downstream effector DEPDC1 as drivers of pulmonary vascular cell hyper-proliferation and remodeling in PAH, demonstrating that smooth muscle-specific DLGAP5 knockdown attenuates pulmonary hypertension and right ventricular hypertrophy in mice.
Smooth muscle DLGAP5 knockdown attenuates experimental PH; hypothesis-generating for targeted therapy in human PAH, clinical validation needed.
Background Pulmonary arterial hypertension (PAH) manifests by pulmonary vascular remodeling, caused by hyper-proliferation and apoptosis resistance of resident PA cells, elevated right ventricular (RV) afterload, and death of RV failure. The goal of this study is to determine the role and mechanisms of action of mitotic spindle-associated microtubule regulator DLG associated protein 5 (DLGAP5) in pulmonary vascular remodeling in PAH. Methods DLGAP5 expression was assessed in human PAH transcriptomic datasets, PAH patients’ lung tissues, pulmonary artery smooth muscle cells (PASMCs), and pulmonary artery adventitial fibroblasts (PAAFs). Loss-of-function, molecular, functional, RNAseq, and network analyses were performed. Smooth muscle (SM)-specific DLGAP5 knockdown using adeno-associated virus serotype 6 (AAV6) in mice with SU5416/hypoxia-induced PH was performed. Results DLGAP5 was overaccumulated in small muscular PAs, PASMCs, and PAAFs from PAH lungs. siRNA DLGAP5 down-regulated cyclin A2, suppressed hyper-proliferation, increased pro-apoptotic BIM, and induced apoptosis in human PAH PASMCs and PAAFs. DEP domain containing 1 (DEPDC1) was identified and validated as a downstream effector of DLGAP5 in PAH PASMCs responsible for hyper-proliferation and apoptosis resistance of human PAH PASMCs. SM-specific DLGAP5 knockdown with AAV6- enTagln -shDLGAP5 reversed DEPDC1 overaccumulation in small muscular PAs, reduced PA medial thickness, RV systolic pressure, mean PA pressure, and RV hypertrophy in mice with SuHx-induced PH. Conclusions DLGAP5 supports proliferation and survival of human PAH PASMCs and PAAFs through up-regulation of cyclin A2, DEPDC1, and suppression of BIM, and promotes PA remodeling and PH in mice. DLGAP5 could serve as a potential molecular target to attenuate pulmonary vascular remodeling in PAH.
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Dey et al. (2026) studied Pulmonary arterial hypertension (PAH). Smooth muscle-specific DLGAP5 knockdown (AAV6-enTagln-shDLGAP5) and siRNA DLGAP5 vs. Matched scrambled control shRNA (AAV6-enTagln-shContr) or control siRNA was evaluated on Pulmonary artery medial thickness, right ventricular systolic pressure, mean pulmonary artery pressure, and right ventricular hypertrophy (p=<0.05). Smooth muscle-specific DLGAP5 knockdown via AAV6-enTagln-shDLGAP5 significantly reduced PA medial thickness, RV systolic pressure, mean PA pressure, and RV hypertrophy in mice with SuHx-induced PH.
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