Targeting Myadm to Intervene Pulmonary Hypertension on Rats Before Pregnancy Alleviates the Effect on Their Offspring’s Cardiac-Cerebral Systems

Abstract

Pregnancy with pulmonary hypertension (PH) seriously threatens the life and safety of mothers and infants. Here, the long-term effect of maternal PH on the postpartum growth of rat offspring was focused for the first time, as well as explored the role of Myadm in PH rats before pregnancy based upon the previous findings. Patients with PH are prone to hypoxemia, leading to insufficient placental structure and function, which affects the organ function of fetuses, followed by evidence that differently expressed genes (DEGs) existed in the heart of maternal PH newborn rats and enriched in pathways related to cardiac and nerve development on human infants with similar birth outcome: low birth weight (LBW). LBW was one of the possible birth outcomes of pregnancy with PH, especially severe PH, accompanied by evidence that offspring derived from mothers with PH presented lower birth weights and slower growth rates than those derived from normal control mothers in a rat model. Besides, maternal PH rat offspring showed cardiac remodeling and a significant elevation of the expression levels of hypoxia- and inflammation-related markers in the cerebral cortex at both 10 and 14 weeks of age, respectively. What is more, the previous studies found that the overexpression of Myadm could result in the remodeling of the pulmonary artery. And targeting Myadm to intervene PH before pregnancy could alleviate sustained low weight growth in maternal PH rat offspring, and the pathological changes of the cardiac–cerebral system caused by maternal PH, including enlarged right heart cavity, loss of cardiomyocytes, abnormal heart index, as well as cerebral cortex hypoxia and the inflammatory state as they grew up to a certain extent. The findings show the pathological significance of maternal PH on offspring growth and the cardiac–cerebral development in a rat model, as well as point out the potential treatment target, which may provide a further reference for pregnancy outcomes in women with PH and healthy development of offspring to some extent.

Smooth Muscle Ythdf2 Abrogation Ameliorates Pulmonary Vascular Remodeling by Regulating Myadm Transcript Stability

“…It has a close association with various cardio-pulmonary diseases, including asthma, hypertension, and PH. 20,30,31 Targeting Myadm has been confirmed to improve hypoxia-induced PH and mitigate the detrimental effects on the cardiac-cerebral development of offspring from maternal PH in rats. 18,20 Furthermore, overexpression of Myadm in PASMCs can promote the expression of cell cycle-related proteins, such as PCNA, Cyclin D1, and CDK2, while concurrently inhibiting the cell cycle kinase inhibitor p21 by promoting Klf4 nuclear export, all of which provides a basis for the excessive proliferation of PASMCs in PH.…”

“…ActD indicates actinomycin D; cKO, Ythdf2 SM22α Cre , Df2-OE, Ythdf2-overexpression; EdU, 5-ethynyl-2-deoxyuridine; M3-OE, Mettl3-overexpression; My-si, Myadm siRNA; mPASMCs, mouse pulmonary artery smooth muscle cells; PDGF, platelet-derived growth factor; RT-qPCR, real-time quantitative polymerase chain reaction; WT, Ythdf2 floxed ; and Ythdf2, YTH N6-methyladenosine RNA binding protein 2. 20,30,31 Targeting Myadm has been confirmed to improve hypoxia-induced PH and mitigate the detrimental effects on the cardiac-cerebral development of offspring from maternal PH in rats. 18,20 Furthermore, overexpression of Myadm in PASMCs can promote the expression of cell cycle-related proteins, such as PCNA, Cyclin D1, and CDK2, while concurrently inhibiting the cell cycle kinase inhibitor p21 by promoting Klf4 nuclear export, all of which provides a basis for the excessive proliferation of PASMCs in PH.…”

“…20,30,31 Targeting Myadm has been confirmed to improve hypoxia-induced PH and mitigate the detrimental effects on the cardiac-cerebral development of offspring from maternal PH in rats. 18,20 Furthermore, overexpression of Myadm in PASMCs can promote the expression of cell cycle-related proteins, such as PCNA, Cyclin D1, and CDK2, while concurrently inhibiting the cell cycle kinase inhibitor p21 by promoting Klf4 nuclear export, all of which provides a basis for the excessive proliferation of PASMCs in PH. 19 In this study, Myadm was identified as a target gene of Ythdf2 based on multiomics sequencing analysis and its biological functions in PASMC proliferation.…”

“…Among the identified proteins, Myadm was chosen as a focal point for this study due to its significant role in promoting PASMC proliferation in PH. [18][19][20] Previous research has demonstrated that Myadm facilitates PASMC proliferation by suppressing the expression of the cell cycle kinase inhibitor p21. 19 Here, as shown in Figure 5B, the protein expression level of Myadm was lower in PASMCs from Ythdf2 SM22α Cre mice versus PASMCs from Ythdf2 floxed mice in the absence or presence of PDGF, followed by a significant increase in the expression level of p21 (Figure 5C).…”

Myeloid-associated differentiation marker is associated with type 2 asthma and is upregulated by human rhinovirus infection

“…While MYADM was first discovered in hematopoietic progenitor cells, additional studies have noted MYADM gene expression in human spleen, lung, liver, kidney, testis, prostate, skeletal muscle, ovary, and peripheral blood leukocytes (2). Several mechanisms have been described, which indicate that MYADM influences cell physiology and is involved in the pathogenesis of diseases such as cancer (3)(4)(5)(6) and hypertension (7)(8)(9)(10). MYADM is also involved in cell membrane organization for cell spreading and migration by recruiting Rac1 to the membrane raft in HeLa cells (11).…”