Id proteins are critical downstream effectors of BMP signaling in human pulmonary arterial smooth muscle cells

Abstract

bone morphogenetic protein type II receptor; cell cycle; Id; pulmonary arterial smooth muscle cell; pulmonary hypertension PULMONARY ARTERIAL HYPERTENSION (PAH) is a severe clinical condition associated with a poor prognosis and high mortality. Occlusive remodeling of the distal pulmonary vasculature is the major pathological finding in PAH. Proliferation of myofibroblasts and smooth muscle cells in the pulmonary arterial wall increases pulmonary vascular resistance and elevates pulmonary arterial pressure, ultimately leading to right ventricular failure and eventually death (20,26,29). A greater understanding of the molecular mechanisms involved in pulmonary vascular remodeling will facilitate new approaches for therapy.Bone morphogenetic protein type II receptor (BMPR-II) mutations are responsible for the majority (Ͼ70%)of cases of heritable PAH and have been reported in 15-40% of apparently sporadic idiopathic cases (6, 15, 34). Loss of BMPR-II or dysfunction of BMP signaling are now recognized in several preclinical models of PAH, including those induced by hypoxia, monocrotaline, and high flow (10, 16). BMPs are pleiotropic cytokines involved in a wide range of vascular cell function including proliferation, migration, differentiation, and apoptosis, but how BMPR-II mutations cause these abnormalities remains uncertain.The inhibitor of DNA binding family of proteins (Id proteins) are major downstream mediators of BMP signaling (19). Id proteins are basic helix-loop-helix transcription factors that lack a DNA binding domain. These proteins bind to the ubiquitously expressed E protein family members with high affinity and inhibit their binding to target DNA (5, 11). This special function of Id proteins confers a central role in the regulation of gene expression and hence cell differentiation and proliferation (24,31). Until now, four members of the Id family, Id1-4, have been identified in mammalian cells. They are encoded by separate genes and demonstrate individual expression patterns and protein structure, which may contribute to their different functions. For example, Id2 is largely expressed in immune cells (8,40), and only Id1 lacks the consensus CDK2 phosphorylation site at its NH 2 terminus (5). Our recent study revealed that Id1 and Id2 are induced by BMPs in pulmonary artery smooth muscle cells (PASMCs) through a canonical Smad-dependent pathway (37) and that BMPR-II mutation reduced the BMP-stimulated induction of Id1 and Id2 in these cells. We further showed that Id1 and Id2 are involved in the inhibition of PASMC proliferation by BMP4. We have also shown that agents enhancing BMP/ Smad/Id signaling in PASMCs can restore the growth-suppressive effects of BMPs in BMPR-II mutant cells (38,39).In the present study, we undertook a systematic analysis of the regulation of Id1-4 in PASMCs via a range of growth factors, cytokines, and BMPs. Having identified Id1 and Id3 as major targets of BMP signaling in these cells, we show that the induction of both Id1 and Id3 is dependent on intact BMPR-II and that...

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

“…62 ID3 is a transcription factor that is upregulated in its expression in the pulmonary vasculature following chronic hypoxia. 65 Of interest, the experimental overexpression of ID3 in endothelial cells inhibits apoptosis and increases the expression of VEGFR3. 58 Thus, these data are consistent with the hypothesis that long-lasting Sugen 5416-triggered VEGFR1 and VEGFR2 blockade can activate in endothelial cells a stem cell-related cell proliferation mechanism 62 that includes VEGFR3 protein expression.…”

Inhibition of Nuclear Factor-κB in the Lungs Prevents Monocrotaline-Induced Pulmonary Hypertension in Mice

“…In addition, we observed a new association between NF-κB and Id protein which is now considered to be a novel player in PAH. 33 Id proteins (Id1-Id4) are major downstream transcriptional targets of BMP signaling. 34 We and others have previously identified the Id family of transcription factors as important functional targets of BMP signaling, with relevance to PAH.…”

Loss of MicroRNA-17∼92 in Smooth Muscle Cells Attenuates Experimental Pulmonary Hypertension via Induction of PDZ and LIM Domain 5

“…Interestingly, PDLIM5 can bind to Inhibitors of Differentiation 2 (ID2) and sequester it in the cytoplasm, inhibiting Id2 activity (59,60). Because ID family proteins are well implicated in BMP signaling and PAH (66,67), it will be of interest to investigate whether PDLIM5 regulates Smad nuclear/cytosol in an ID-dependent pathway. Alternatively, PDLIM5 may regulate Smad phosphorylation by protein kinase C, as PDLIM5 also recruit activated protein kinase C and its substrates to promote phosphorylation (57,61,62).…”