MicroRNA-34a: the bad guy in age-related vascular diseases

Abstract

The age-related vasculature alteration is the prominent risk factor for vascular diseases (VD), namely, atherosclerosis, abdominal aortic aneurysm, vascular calcification (VC) and pulmonary arterial hypertension (PAH). The chronic sterile low-grade inflammation state, alias inflammaging, characterizes elderly people and participates in VD development. MicroRNA34-a (miR-34a) is emerging as an important mediator of inflammaging and VD. miR-34a increases with aging in vessels and induces senescence and the acquisition of the senescence-associated secretory phenotype (SASP) in vascular smooth muscle (VSMCs) and endothelial (ECs) cells. Similarly, other VD risk factors, including dyslipidemia, hyperglycemia and hypertension, modify miR-34a expression to promote vascular senescence and inflammation. miR-34a upregulation causes endothelial dysfunction by affecting ECs nitric oxide bioavailability, adhesion molecules expression and inflammatory cells recruitment. miR-34a-induced senescence facilitates VSMCs osteoblastic switch and VC development in hyperphosphatemia conditions. Conversely, atherogenic and hypoxic stimuli downregulate miR-34a levels and promote VSMCs proliferation and migration during atherosclerosis and PAH. MiR34a genetic ablation or miR-34a inhibition by anti-miR-34a molecules in different experimental models of VD reduce vascular inflammation, senescence and apoptosis through sirtuin 1 Notch1, and B-cell lymphoma 2 modulation. Notably, pleiotropic drugs, like statins, liraglutide and metformin, affect miR-34a expression. Finally, human studies report that miR-34a levels associate to atherosclerosis and diabetes and correlate with inflammatory factors during aging. Herein, we comprehensively review the current knowledge about miR-34a-dependent molecular and cellular mechanisms activated by VD risk factors and highlight the diagnostic and therapeutic potential of modulating its expression in order to reduce inflammaging and VD burn and extend healthy lifespan.

Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases

“…A recent review generalized the role of miR-34a in vascular aging and senescence, demonstrating that miR-34a promoted vascular aging through targeting SIRT1 or regulating vascular cell adhesion protein1 and intercellular adhesion molecule 1 at least partially (55). More importantly, activation of FOXO3 promoted stress resistance in differentiated human vascular endothelial and smooth muscle cells which related to cellular aging (56).…”

The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities

“…It is becoming a vital mediator of inflammation and VD. This is because microRNA34a expression increases with vascular ageing, and it causes VSMCs and ECs to acquire the SASP [ 109 ]. It has been reported that senescent cells have this specific secretory phenotype that alters the homeostasis of surrounding tissues and the environment.…”

Transcriptional and Epigenetic Factors Associated with Early Thrombosis of Femoral Artery Involved in Arteriovenous Fistula

“…Since oxidative stress, hypoxia, and VSMC proliferation play a critical role in AVF maturation/failure, these miRNAs might play an important role. The levels of miR-34a-5p, associated with atherosclerosis and miR-34a-5p, play a crucial role in inflammatory pathology [ 67 ] and various studies [ 68 , 69 ] have discussed miR-34a-5p, which was found to be inhibited in this study, as a potential therapeutic target in cardiovascular disease. miR-205-5p, which was found to be activated in this study, suppresses the proliferation of pulmonary VSMCs [ 70 ], whereas miR-153, which was found to be inhibited in this study, attenuates hypoxia-induced excessive proliferation and migration of pulmonary arterial SMCs [ 71 ].…”