Vascular remodeling process in pulmonary arterial hypertension, with focus on miR-204 and miR-126 (2013 Grover Conference series)

Abstract

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized primarily by increased proliferation and resistance to apoptosis in distal pulmonary arteries. Previous literature has demonstrated that the transcription factors NFAT (nuclear factor of activated T cells) and HIF-1α (hypoxia inducible factor 1α) are extensively involved in the pathogenesis of this disease and, more recently, has implicated STAT3 (signal transducer and activator of transcription 3) in their activation. Novel research shows that miR-204, a microRNA recently found to be notably downregulated through induction of PARP-1 (poly [ADP-ribose] polymerase 1) by excessive DNA damage in PAH, inhibits activation of STAT3. Contemporary research also indicates systemic impairment of skeletal muscle microcirculation in PAH and attributes this to a debilitated vascular endothelial growth factor pathway resulting from reduced miR-126 expression in endothelial cells. In this review, we focus on recent research implicating miR-204 and miR-126 in vascular remodeling processes, data that allow a better understanding of PAH molecular pathways and constitute a new hope for future therapy.

Keywords: angiogenesis; microRNA; pulmonary arterial hypertension; skeletal muscle; vascular remodeling.

Figure 1

Molecular contribution of pulmonary artery smooth muscle cells (PASMC) to pulmonary arterial hypertension (PAH) phenotype (HIF-1α, NFAT, STAT3): cross links between the major molecular actors implicated in establishment of the PAH-PASMC phenotype. PDGF: platelet-derived growth factor; ET-1: endothelin-1; IL-6: interleukin-6; NFAT: nuclear factor of activated T cells; STAT3: signal transducer and activator of transcription 3; HIF-1α: hypoxia inducible factor 1α; Pim-1: provirus integration site for Moloney murine leukemia virus; KLF5: Krüppel-like factor 5; Bad: Bcl-2-associated death promoter; BMPR2: bone morphogenetic protein receptor type II; Bcl-2: B-cell lymphoma 2; HXK2: hexokinase-2; ROS: reactive oxygen species; PDK: pyruvate dehydrogenase kinase; [K⁺]i: intracellular [K⁺]; [Ca²⁺]i: intracellular [Ca²⁺]; PPAR: peroxisome proliferator-activated receptor; PDH: pyruvate dehydrogenase. Blue arrows indicate activation and red arrows repression.

Figure 2

Key role played by miR-204 in pulmonary arterial hypertension pulmonary artery smooth muscle cell phenotype: proposed model of DNA damage leading to miR-204 reduction implicated in STAT3, NFAT, and HIF-1α upregulation. PARP-1: poly (ADP-ribose) polymerase 1; miR: microRNA; STAT3: signal transducer and activator of transcription 3; RUNX2: Runt-related transcription factor 2; HIF-1α: hypoxia inducible factor 1α; NFATC2: nuclear factor of activated T cells, cytoplasmic 2. Blue arrows indicate activation and red arrows repression.

Figure 3

Pulmonary arterial hypertension (PAH) pathology on systemic angiogenesis. Microcirculation impairment in peripheral skeletal muscle and the right ventricle is associated with miR-126 expression downregulation and SPRED-1 upregulation. VEGF: vascular endothelial growth factor; miR: microRNA; VEGFR-2: vascular endothelial growth factor receptor 2; P-RAF: phosphorylated RAF; SPRED-1: Sprouty-related, EVH1 domain–containing protein 1; P-ERK: phosphorylated extracellular signal-regulated kinase. Blue arrows indicate activation and red arrows expression.