Molecular mechanism of miR-181b in heart disease due to pregnancy-induced hypertension syndrome

Abstract

The present study aimed to investigate the molecular mechanisms of microRNA (miR)-181b in heart disease due to hypertensive disorders complicating pregnancy (HDCP) through regulating the expression of metallopeptidase inhibitor 3 (TIMP3). miR-181b expression was detected by reverse transcription-quantitative polymerase chain reaction in peripheral blood samples from patients with HDCP. These samples were analyzed for clinical pathological characteristics. The primary cardiomyocytes of rats were cultured in hypoxic conditions for 24 h, in which miR-181b expression was detected at different time points. The expression of TIMP3 was assessed in normal rat cardiomyocytes following transfection with miR-181b mimics by western blot analysis. The TIMP3 protein was also detected in cardiomyocytes following transfection with TIMP3 short interfering-RNA. The apoptosis rate of transfected cardiomyocytes was detected by flow cytometry following 24 h of culture in a hypoxic environment. Luciferase assay was applied to validate whether miR-181b binds to the 3′ untranslated region of TIMP3 mRNA. miR-181b expression was significantly downregulated in the peripheral blood of patients with HDCP and the miR-181b expression was negatively associated with the grades of hypertension (P<0.05). The results of luciferase assay indicated that miR-181b directly targets TIMP3. The apoptosis rates of rat cardiomyocytes in the group transfected with miR-181b or TIMP3 siRNA was significantly lower than the normal control group (P<0.05). miR-181b may inhibit apoptosis of cardiomyocytes to protect myocardial cells through directly targeting TIMP3 genes, which serve important roles in HDCP.

Biology of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), and Its Therapeutic Implications in Cardiovascular Pathology

“…Through binding to, and inhibiting Timp3 expression, miR-21 enhances survival, migration and capillary formation ability of human umbilical vein endothelial cell lines (HUVECs) (Hu et al, 2016). miR-181b targets Timp3 and reduces apoptosis of cardiomyocytes (Gao et al, 2017), but enhances gelatinases/MMP activity in human aortic valve endothelial cells which may contribute to calcific aortic valve disease (Heath et al, 2018). MiR-181b is increased in human atherosclerotic plaques and abdominal aortic aneurysms (AAA), and inhibition of miR-181b suppressed the development and progression of atherosclerosis and aneurysms through increasing expression of TIMP3, elastin, and collagen (Di Gregoli et al, 2017).…”

“…Since in vitro experiments lack the multicellular interactions that exist in vivo, the results from in vitro studies may differ from those in vivo. An in vitro study showed that silencing TIMP3 reduces apoptosis of cardiomyocytes isolated from 5 to 6 week-old female rats (Gao et al, 2017). However, deficiency or inhibition of TIMP3 enhances neonatal mouse cardiomyocyte proliferation in vitro and in vivo, which can be inhibited by treatment with recombinant TIMP3, through a mechanism involving inhibition of MMP activity and EGFR/JNK/SP-1 signaling pathway (Hammoud et al, 2009;Shi et al, 2017).…”

Circ_ZNF512-Mediated miR-181d-5p Inhibition Limits Cardiomyocyte Autophagy and Promotes Myocardial Ischemia/Reperfusion Injury through an EGR1/mTORC1/TFEB-Based Mechanism

“…miR-181a has been confirmed to be cardioprotective under myocardial infarction stress by reducing aldosterone-mineralocorticoid receptor-mediated cardiac remodeling . Moreover, miR-181b inhibits the apoptosis of cardiomyocytes and protects cardiomyocytes in heart disease due to pregnancy-induced hypertension syndrome . miR-181 can directly target early growth response 1 (EGR1), which is an immediate master regulator gene conferring an integral role in the pathophysiology of various cardiovascular diseases …”

Role of miR‐106‐mediated mitogen‐activated protein kinase signaling pathway in oxidative stress injury and inflammatory infiltration in the liver of the mouse with gestational hypertension

“…miRNA is a noncoding RNA, which can regulate downstream signaling pathway and thereby regulate the relevant biological activities 25–29. In the present study, the blood pressure in the miR‐106a‐mimic group was lower than in the model group, revealing that miR‐106a overexpression can reduce the blood pressure of GH mice.…”