Critical miRNAs in regulating pulmonary hypertension: A focus on Signaling pathways and therapeutic Targets.

Pulmonary hypertension (PH) is complex disease as a result of obstructive pulmonary arterial remodeling, which in turn results in elevated pulmonary arterial pressure (PAP) and subsequent right ventricular heart failure, eventually leading to premature death. However, there is still a lack of a diagnostic blood-based biomarker and therapeutic target for PH. Because of the difficulty of diagnosis, new and more easily accessible prevention and treatment strategy are being explored. New target and diagnosis biomarkers should also allow for early diagnosis. In biology, miRNAs are short endogenous RNA molecules that are not coding. It is known that miRNAs can regulate gene expression and affect a variety of biological processes. Besides, miRNAs have been proven to be a crucial factor in PH pathogenesis. miRNAs have various effects on pulmonary vascular remodeling and are expressed differentially in various pulmonary vascular cells. Nowadays, it has been shown to be critical in the functions of different miRNAs in the pathogenesis of PH. Therefore, clarifying the mechanism of miRNAs regulating pulmonary vascular remodeling is of great importance to explore new therapeutic targets of PH and improve the survival qualify and time of patients. This review is focused on the role, mechanism, and potential therapeutic targets of miRNAs in PH and puts forward possible clinical treatment strategies.

Mammalian Target of Rapamycin as the Therapeutic Target of Vascular Proliferative Diseases: Past, Present, and Future.

ABSTRACT: The abnormal proliferation of vascular smooth muscle cells (VSMCs) is a key pathological characteristic of vascular proliferative diseases. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays an important role in regulating cell growth, motility, proliferation, and survival, as well as gene expression in response to hypoxia, growth factors, and nutrients. Increasing evidence shows that mTOR also regulates VSMC proliferation in vascular proliferative diseases and that mTOR inhibitors, such as rapamycin, effectively restrain VSMC proliferation. However, the molecular mechanisms linking mTOR to vascular proliferative diseases remain elusive. In our review, we summarize the key roles of the mTOR and the recent discoveries in vascular proliferative diseases, focusing on the therapeutic potential of mTOR inhibitors to target the mTOR signaling pathway for the treatment of vascular proliferative diseases. In this study, we discuss mTOR inhibitors as promising candidates to prevent VSMC-associated vascular proliferative diseases.

Targeting Vascular Smooth Muscle Cell Senescence: A Novel Strategy for Vascular Diseases.

Vascular diseases are a major threat to human health, characterized by high rates of morbidity, mortality, and disability. VSMC senescence contributes to dramatic changes in vascular morphology, structure, and function. A growing number of studies suggest that VSMC senescence is an important pathophysiological mechanism for the development of vascular diseases, including pulmonary hypertension, atherosclerosis, aneurysm, and hypertension. This review summarizes the important role of VSMC senescence and senescence-associated secretory phenotype (SASP) secreted by senescent VSMCs in the pathophysiological process of vascular diseases. Meanwhile, it concludes the progress of antisenescence therapy targeting VSMC senescence or SASP, which provides new strategies for the prevention and treatment of vascular diseases.

Upregulation of eIF2α by m6A modification accelerates the proliferation of pulmonary artery smooth muscle cells in MCT-induced pulmonary arterial hypertension rats.

Pulmonary arterial hypertension (PAH) is a malignant cardiovascular disease. Eukaryotic initiation factor 2α (eIF2α) plays an important role in the proliferation of pulmonary artery smooth muscle cells (PASMCs) in hypoxia-induced pulmonary hypertension (HPH) rats. However, the regulatory mechanism of eIF2α remains poorly understood in PAH rats. Here, we discover eIF2α is markedly upregulated in monocrotaline (MCT)-induced PAH rats, eIF2α can be upregulated by mRNA methylation, and upregulated eIF2α can promote PASMC proliferation in MCT-PAH rats. GSK2606414, eIF2α inhibitor, can downregulate the expression of eIF2α and alleviate PASMC proliferation in MCT-PAH rats. And we further discover the mRNA of eIF2α has a common sequence with N 6-methyladenosine (m6A) modification by bioinformatics analysis, and the expression of METTL3, WTAP, and YTHDF1 is upregulated in MCT-PAH rats. These findings suggest a potentially novel mechanism by which eIF2α is upregulated by m6A modification in MCT-PAH rats, which is involved in the pathogenesis of PAH.

Microglia-associated neuroinflammation is a potential therapeutic target for ischemic stroke.

Microglia-associated neuroinflammation plays an important role in the pathophysiology of ischemic stroke. Microglial activation and polarization, and the inflammatory response mediated by these cells play important roles in the development, progression and outcome of brain injury after ischemic stroke. Currently, there is no effective strategy for treating ischemic stroke in clinical practice. Therefore, it is clinically important to study the role and regulation of microglia in stroke. In this review, we discuss the involvement of microglia in the neuroinflammatory process in ischemic stroke, with the aim of providing a better understanding of the relationship between ischemic stroke and microglia.

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases.

The dynamic balance of cardiomyocytes and neurons is essential to maintain the normal physiological functions of heart and brain. If excessive cells die in tissues, serious Cardio-Cerebrovascular Diseases would occur, namely, hypertension, myocardial infarction, and ischemic stroke. The regulation of cell death plays a role in promoting or alleviating Cardio-Cerebrovascular Diseases. Ferroptosis is an iron-dependent new type of cell death that has been proved to occur in a variety of diseases. In our review, we focus on the critical role of ferroptosis and its regulatory mechanisms involved in Cardio-Cerebrovascular Diseases, and discuss the important function of ferroptosis-related inhibitors in order to propose potential implications for the prevention and treatment of Cardio-Cerebrovascular Diseases.

Interleukin-6: A Novel Target for Cardio-Cerebrovascular Diseases.

Cardio-Cerebrovascular Disease is a collective term for cardiovascular disease and cerebrovascular disease, being a serious threat to human health. A growing number of studies have proved that the content of inflammatory factors or mediators determines the stability of vascular plaque and the incidence of cardio-cerebrovascular event, and involves in the process of Cardio-Cerebrovascular Diseases. Interleukin-6 is a widely used cytokine that causes inflammation and oxidative stress, which would further result in cardiac and cerebral injury. The increased expression of interleukin-6 is closely related to atherosclerosis, myocardial infarction, heart failure and ischemic stroke. It is a key risk factor for these diseases by triggering inflammatory reaction and inducing other molecules release. Therefore, interleukin-6 may become a potential target for Cardio-Cerebrovascular Diseases in the future. This paper is aimed to discuss the expression changes and pathological mechanisms of interleukin-6 in Cardio-Cerebrovascular Diseases, and to provide a novel strategy for the prevention and treatment of Cardio-Cerebrovascular Diseases.

Pulmonary Artery Smooth Muscle Cell Senescence Promotes the Proliferation of PASMCs by Paracrine IL-6 in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a critical and dangerous disease in cardiovascular system. Pulmonary vascular remodeling is an important pathophysiological mechanism for the development of pulmonary arterial hypertension. Pulmonary artery smooth muscle cell (PASMC) proliferation, hypertrophy, and enhancing secretory activity are the main causes of pulmonary vascular remodeling. Previous studies have proven that various active substances and inflammatory factors, such as interleukin 6 (IL-6), IL-8, chemotactic factor for monocyte 1, etc., are involved in pulmonary vascular remodeling in PH. However, the underlying mechanisms of these active substances to promote the PASMC proliferation remain to be elucidated. In our study, we demonstrated that PASMC senescence, as a physiopathologic mechanism, played an essential role in hypoxia-induced PASMC proliferation. In the progression of PH, senescence PASMCs could contribute to PASMC proliferation via increasing the expression of paracrine IL-6 (senescence-associated secretory phenotype). In addition, we found that activated mTOR/S6K1 pathway can promote PASMC senescence and elevate hypoxia-induced PASMC proliferation. Further study revealed that the activation of mTOR/S6K1 pathway was responsible for senescence PASMCs inducing PASMC proliferation via paracrine IL-6. Targeted inhibition of PASMC senescence could effectively suppress PASMC proliferation and relieve pulmonary vascular remodeling in PH, indicating a potential for the exploration of novel anti-PH strategies.

miR-100 suppresses mTOR signaling in hypoxia-induced pulmonary hypertension in rats.

Mammalian Target of Rapamycin (mTOR) is involved in the proliferation and survival of pulmonary artery smooth muscle cells (PASMCs) in human pulmonary hypertension (PH) and animal PH models, and miRNAs are reported to play a key role in modulation of the proliferation of PASMCs. The purposes of this study are to determine the functions of miR-100 and mTOR in cardiovascular remodeling of the hypoxic PH rats and to clarify the correlation between them. We established a rat model of hypoxic PH, which showed an increase in right ventricle systolic pressure, right ventricular and pulmonary vascular remodeling, accompanied by an up-regulation of mTOR and a down-regulation of miR-100. Next, we established an in vitro model of hypoxia-induced proliferation of PASMCs. Consistent with the in vivo findings, hypoxia induced proliferation of PASMCs, accompanied by a down-regulation of miR-100 and an up-regulation of mTOR; these phenomena were reversed by miR-100 mimics or the antagonist of mTOR. Finally, the dual-luciferase reporter gene assay was utilized to reveal the direct interaction between miR-100 and the 3 '-UTR region of mTOR gene. Based on these observations, we conclude that miR-100 can modulate the proliferation of PASMCs in hypoxic PH rats through suppressing the mTOR expression.