MicroRNA-425 and microRNA-155 cooperatively regulate atrial natriuretic peptide expression and cGMP production

Abstract

AimsAtrial natriuretic peptide (ANP), secreted primarily by atrial cardiomyocytes, decreases blood pressure by raising cyclic 3’,5’-guanosine monophosphate (cGMP) levels and inducing vasorelaxation, natriuresis, and diuresis. Raising the level of ANP has been shown to be an effective treatment for hypertension. To advance the future development of an anti-microRNA (miR) approach to increasing expression of ANP, we investigated the regulation of NPPA expression by two miRs: miR-425 and miR-155. We examined whether miR-425 and miR-155 have an additive effect on the expression and function of ANP.Methods and resultsHuman embryonic stem cell-derived cardiomyocytes (hESC-CMs) were transfected with miR-425, miR-155, or a combination of the two miRs. Two days later, NPPA expression was measured using real time qPCR. Each of the miRs decreased NPPA expression over a wide range of concentrations, with a significant reduction at concentrations as low as 1 nM. The combination of miR-425 and miR-155 reduced NPPA expression to a greater extent than either miR-425 or miR-155 alone. An in vitro assay was developed to study the potential biological significance of the miR-induced decrease in NPPA expression. The cooperative effect of miR-425 and miR-155 on NPPA expression was associated with a significant decrease in cGMP levels.ConclusionsThese data demonstrate that miR-425 and miR-155 regulate NPPA expression in a cooperative manner. Targeting both miRNAs with anti-miRs (possibly at submaximal concentrations) might prove to be a more effective strategy to modulate ANP levels, and thus blood pressure, than targeting either miRNA alone.

Natriuretic peptide pathways in heart failure: further therapeutic possibilities

“…Micro-RNA 425 and/or 155 (mir425 and/or mir155), which downregulate ANP gene expression and production, may be elevated in HF. 66 , 67 Moreover, Celik et al . 68 reported a cis -acting ANP antisense transcript (ANP-AS), negatively regulating ANP expression in human cardiomyocytes, which was increased in heart tissue of patients with advanced HF.…”

Guanylyl cyclase/natriuretic peptide receptor-A: Identification, molecular characterization, and physiological genomics

“…The deletion of carboxyl-terminus regions of GC-A/NPRA suggested that the specific sequence in catalytic GCCD and protein-KHD played a pivotal role in the internalization, sequestration, and metabolic degradation of the receptor protein ( Pandey et al, 2000 ; Pandey, 2015 ). Interestingly, several studies have indicated that micro-RNA (miR) plays critical roles in the regulatory mechanisms and function of ANP/NPRA system ( Arora et al, 2013 ; Somanna et al, 2013 ; Wu et al, 2016 ; Vandenwijngaert et al, 2018 ; Khurana et al, 2022 ). Our recent findings have suggested that prolonged ANP treatments along with miR-128 and miR195 of cultured cells expressing high density of GC-A/NPRA caused downregulation of the receptor in a time-and dose-dependent manner ( Khurana et al, 2022 ).…”

Role of brain natriuretic peptide in the pathogenesis of resistant hypertension

“…Аллели, связанные с повышенными концентрациями НУП, также были связаны с более низким кровяным давлением и снижением вероятности развития АГ [23]. Недавно было показано, что микроРНК (miR-425) отрицательно регулирует продукцию ANP, а распространенный генетический вариант делает продукцию ANP устойчивой к miR-425 [24]. В исследовании у афроамериканцев циркулирующие концентрации NT-proBNP после поправки на клинические ковариаты были на 40% ниже, чем у представителей европеоидной расы, что может быть частично связано с генетической изменчивостью [25].…”