PDE-5-Inhibited BMSCs Alleviate High Glucose-Induced Myocardial Fibrosis and Cardiomyocyte Apoptosis by Activating the cGMP/PKG Pathway

¹ Geriatric Medicine Center, Department of Endocrinology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310014 Hangzhou, Zhejiang, China

² Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, 310014 Hangzhou, Zhejiang, China

³ Jinzhou Medical University, 121001 Jinzhou, Liaoning, China

⁴ Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, 310014 Hangzhou, Zhejiang, China

^*Correspondence: feixianming@hmc.edu.cn (Xianming Fei)

Front. Biosci. (Landmark Ed) 2023, 28(7), 155; https://doi.org/10.31083/j.fbl2807155

Submitted: 4 November 2022 | Revised: 10 January 2023 | Accepted: 12 January 2023 | Published: 28 July 2023

(This article belongs to the Special Issue Molecular Signaling Pathways Regulating Cell Survival, Death and Differentiation)

This is an open access article under the CC BY 4.0 license.

Abstract

Background: Phosphodiesterase-5 (PDE-5) inhibitors have been found to play an important cardio-protective role. This study aimed to clarify the inhibitory effects of PDE-5-silenced bone marrow mesenchymal stem cells (BMSCs) on high glucose-induced myocardial fibrosis and cardiomyocyte apoptosis. Methods: Cardiomyocytes and fibroblasts of neonatal rats were treated with high glucose (HG), and co-cultured with PDE-5-overexpressed or -knocked down BMSCs. The viability and apoptosis as well as the levels of cytokines, Cardiac troponin I and Vimentin of cardiomyocytes and fibroblasts were studied. The expressions of PDE-5, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG), in both cells were evaluated. Results: BMSCs that silenced PDE-5 facilitated the viability of cardiomyocytes, decreased the viability of fibroblasts, and inhibited the apoptosis of cardiomyocytes and fibroblasts. The contents of collagen-I, collagen-III, tissue inhibitor of metalloproteinase (TIMP)-1 and Dermin in fibroblasts were decreased by the PDE-5 inhibitor, but the levels of matrix metalloproteinase (MMP)-1 in fibroblasts and troponin-I in cardiomyocytes were increased by the PDE-5 inhibitor. PDE-5 inhibitor also suppressed the expression of PDE-5 but up-regulated cGMP and PKG expression in cardiomyocytes and fibroblasts. Conclusions: PDE-5-inhibited BMSCs can decrease HG-induced myocardial fibrosis and cardiomyocyte apoptosis by activating the cGMP/PKG pathway, and may play a role in the prevention and treatment of diabetic cardiomyopathy.

Keywords

phosphodiesterase-5

BMSCs

diabetic cardiomyopathy

cGMP/PKG pathway

myocardial fibrosis

cardiomyocytes apoptosis

Funding

LGD20H070002/Public Welfare Technology Application Research Project of Zhejiang Province

LGD21H020004/Public Welfare Technology Application Research Project of Zhejiang Province

ZRY2020B014/Research Project of Zhejaing Provincial People’s Hospital

2022KY523/Medicine and Health Science and Technology Project of Zhejiang Province

2020KY022/Medicine and Health Science and Technology Project of Zhejiang Province

2021KY060/Medicine and Health Science and Technology Project of Zhejiang Province

Figures

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Fig. 1.

Isolation and identification of neonatal rat primary cardiomyocytes and fibroblasts. (A) The morphology of rat primary cardiomyocytes and fibroblasts cultured for 4 hours, 24 hours, 48 hours and 72 hours was observed under inverted microscope (magnification, 100 $\times{}$ ). (B) The expression of Cardiac troponin I and Nkx2.5 in rat myocardial cells (magnification, 200 $\times{}$ ). (C) The expression of Vimentin and $\alpha{}$ -SMA in rat fibroblasts (magnification, 200 $\times{}$ ).

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