MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension

Abstract

Loss of the growth-suppressive effects of bone morphogenetic protein (BMP) signaling has been demonstrated to promote pulmonary arterial endothelial cell dysfunction and induce pulmonary arterial smooth muscle cell (PASMC) proliferation, leading to the development of pulmonary arterial hypertension (PAH). MicroRNAs (miRs) mediate higher order regulation of cellular function through coordinated modulation of mRNA targets; however, miR expression is altered by disease development and drug therapy. Here, we examined treatment-naive patients and experimental models of PAH and identified a reduction in the levels of miR-140-5p. Inhibition of miR-140-5p promoted PASMC proliferation and migration in vitro. In rat models of PAH, nebulized delivery of miR-140-5p mimic prevented the development of PAH and attenuated the progression of established PAH. Network and pathway analysis identified SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) as a key miR-140-5p target and regulator of BMP signaling. Evaluation of human tissue revealed that SMURF1 is increased in patients with PAH. miR-140-5p mimic or SMURF1 knockdown in PASMCs altered BMP signaling, further supporting these factors as regulators of BMP signaling. Finally, Smurf1 deletion protected mice from PAH, demonstrating a critical role in disease development. Together, these studies identify both miR-140-5p and SMURF1 as key regulators of disease pathology and as potential therapeutic targets for the treatment of PAH.

The regulatory role of microRNAs in angiogenesis‐related diseases

“…Functionally, elevated miR‐19a can inhibit arteriogenesis by inhibiting Wnt signalling in vitro and in vivo via directly targeting FZD4 and LRP6,81 and miR‐124 play a major role in glycolysis and hyperproliferation of ECs in PAH by regulating PTBP1 and PKM2 36. In recent studies, miR‐135a levels are up‐regulated in PAH mice models, and miR‐204 and miR‐140‐5p levels are down‐regulated in both PAH patient and PAH model 185, 186. Mechanically, miR‐135a inhibitor can lead to cell death and reduced miR‐140‐5p level can enhance proliferation and migration of PASMCs by increasing SMURF1.…”

“…Mechanically, miR‐135a inhibitor can lead to cell death and reduced miR‐140‐5p level can enhance proliferation and migration of PASMCs by increasing SMURF1. Interestingly, miR‐135a inhibitor, miR‐204 mimics or miR‐140‐5p mimics can significantly prevent the development of PAH, respectively 185, 186. Overall, miRNAs play an important role in the development of PAH and in diagnosis and treatment for PAH.…”

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…Importantly, mice with genetic deletions of miR-145 exhibited protection against PH (28). Conversely, miR-140 has been implicated in the regulation of Smad ubiquitination regulatory factor 1 (SMURF1), an E3-ubiquitin protein ligase 1, that in turn modulates BMPR2 signaling and PAH in vivo (29). Numerous additional miRNAs implicated in PAH have been reported to respond to BMPR2 signaling, such as miR-130/301 (19), and to regulate BMPR2 directly, such as miR-21 (30).…”

miRNA-140-5p: New Avenue for Pulmonary Arterial Hypertension Drug Development?

“…We have recently published our research describing reduced levels of miR-140-5p in patients with PAH, and animal models of PAH [17]. Whole blood expression of miR-140-5p correlated with clinical measures of disease severity, and predicted survival.…”

“…We therefore sought to determine whether one of the mechanisms by which miR-140-5p regulates PAH pathogenesis was via suggesting the potential to exploit conventional enzyme inhibitor mechanisms to block substrate ubiquitination [20]. In the context of therapeutic value for PAH patients, an inhibitor for Smurf1 is highly attractive whereby ubiquitination of key substrates within the BMP pathway such as BMPR2 may be inhibited restoring signalling through this key pathway [17]. Compared to a therapeutic miR140-5p mimetic, an inhibitor of Smurf1 may be more tractable where challenges such as rapid miR degradation, low cellular penetration and target engagement particularly in complex remodelled pulmonary vasculature of PAH patients and potential for liver toxicity with miR therapeutics all may limit ability to progress promising molecules to the clinic and ultimately represent barriers to achieving clinical efficacy.…”