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Cell death-inducing DFF45-like effector C gene silencing alleviates pulmonary vascular remodeling in a type 2
Dong-Xin Sui1,2, Hui-Min Zhou1, Feng Wang1
1The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Aims/Introduction:
Cell death-inducing DFF45-like effector C (CIDEC) was proven to be closely associated with the development of insulin resistance and metabolic syndrome. We aimed to investigate whether CIDEC gene silencing could alleviate pulmonary vascular remodeling in a type 2 diabetes rat model.
Materials And Methods:
We built a type 2 diabetes rat model. An adenovirus harboring CIDEC small interfering ribonucleic acid was then injected into the jugular vein to silence the CIDEC gene. After hematoxylin-eosin and Sirius red staining, we detected indexes of the pulmonary arterioles remodeling. Immunohistochemical staining of proliferating cell nuclear antigen was used to evaluate the pulmonary arterial smooth muscle cell proliferation. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling reaction and western blotting. The levels of signaling pathway proteins expression were measured by western blotting analyses.
Results:
Histological analysis of the pulmonary artery showed that the thickness of the adventitia and medial layer increased notably in type 2 diabetes rats. Immunohistochemistry showed that more proliferating cell nuclear antigen-positive pulmonary arterial smooth muscle cells could be seen in type 2 diabetes rats; and after CIDEC gene silencing, proliferating cell nuclear antigen positive cells decreased accordingly. Cleaved caspase-3 and cleaved poly (adenosine diphosphate-ribose) polymerase measured by western blotting showed increased apoptosis with overexpressed CIDEC in diabetes. Terminal deoxynucleotidyl transferase dUTP nick end labeling reaction showed that the apoptosis mainly occurred in endothelial cells. Western blotting analysis showed CIDEC overexpression in rats with diabetes, and phosphorylated adenosine 5' monophosphate-activated protein kinase-α expression was significantly decreased. After CIDEC gene silencing, the expression of phosphorylated adenosine 5' monophosphate-activated protein kinase-α was upregulated.
Conclusions:
The CIDEC/5' monophosphate-activated protein kinase signaling pathway could be a potential therapeutic candidate against pulmonary vascular diseases in type 2 diabetes patients.
Insights
Silencing the CIDEC gene in type 2 diabetes rats reduced pulmonary vascular remodeling and increased apoptosis. This suggests CIDEC is a therapeutic target for diabetic pulmonary vascular diseases.
Area of Science:
- Cardiovascular Biology
- Metabolic Diseases
- Molecular Medicine
Background:
- Cell death-inducing DFF45-like effector C (CIDEC) is linked to insulin resistance and metabolic syndrome.
- Pulmonary vascular remodeling is a complication associated with type 2 diabetes.
Purpose of the Study:
- To investigate the effect of CIDEC gene silencing on pulmonary vascular remodeling in a type 2 diabetes rat model.
- To explore the potential of CIDEC as a therapeutic target for diabetic pulmonary vascular complications.
Main Methods:
- Established a type 2 diabetes rat model and utilized adenovirus-mediated CIDEC small interfering ribonucleic acid (siRNA) for gene silencing.
- Assessed pulmonary arteriole remodeling via histological staining (H&E, Sirius red) and measured smooth muscle cell proliferation using immunohistochemistry.
- Evaluated apoptosis through TUNEL assays and Western blotting for cleaved caspase-3 and PARP.
- Analyzed signaling pathway protein expression, including AMPK, via Western blotting.
Main Results:
- Type 2 diabetes rats exhibited increased pulmonary artery wall thickness and smooth muscle cell proliferation.
- CIDEC gene silencing reduced adventitial and medial thickness and decreased smooth muscle cell proliferation.
- CIDEC overexpression in diabetic rats correlated with increased apoptosis (mainly endothelial cells) and decreased p-AMPK levels.
- Silencing CIDEC upregulated p-AMPK expression, suggesting a role for the CIDEC/AMPK pathway.
Conclusions:
- CIDEC gene silencing alleviates pulmonary vascular remodeling in a type 2 diabetes rat model.
- The CIDEC/AMPK signaling pathway represents a potential therapeutic target for treating pulmonary vascular diseases in type 2 diabetes.
