Background/Purpose: Pulmonary arterial hypertension (PAH) represents a serious co-morbidity affecting up to 10% of systemic sclerosis (SSc) patients. Cardinal features of PAH include inflammation and vascular remodelling, the latter resulting from alterations in proliferation, matrix production, chemokine and cytokine expression by resident cells including pulmonary arterial smooth muscle cells (PASMCs). Previously we have shown an inhibitor of the epigenetic BET bromodomain proteins, JQ1 can antagonise the pro-inflammatory phenotype of SSc dermal fibroblasts. In this study we assessed the role of BET inhibition on PASMC cell contractile to synthetic switching, and the in vivo effects on vascular remodelling and development of PAH in the hypoxia/SU5416 mouse model.

Methods: The effects of siRNA knockdown and pharmacological inhibition using JQ1 on contractile and synthetic PASMCs switching and proliferation, matrix deposition and inflammatory chemokine secretion assessed by crystal violet, Western Blot and ELISA respectively. Using the hypoxia/SU5416 model of PAH, female C57BL/6 mice were maintained in a hypoxic (10% O₂) chamber and given 3 weekly doses of 20mg/kg SU5416 to induce PAH. Animals were treated with JQ1 at 15 or 60 mg/kg/day (n≥6), and haemodynamics, cardiac hypertrophy and vascular remodelling were assessed after 21 days. The effect on circulating inflammatory chemokines was determined by multiplex ELISA. 

Results: Synthetic PASMCs secrete significantly (p<0.05) elevated IL-6, IL-8 and MCP-1 compared to contractile PASMCs (n=3). Administration of JQ1 significantly inhibited in a concentration dependent manner, secretion of MCP1 (P<0.01) and IL-6 (P<0.01) but not IL-8 from PASMCs. Further, elevated collagen type I deposition observed in synthetic PASMCs was significantly inhibited by JQ1. Systemic administration of JQ1 in vivo in the pre-clinical model of hypoxia/SU5416 induced PAH, significantly attenuated right ventricular systemic pressure in a dose dependent manner (P<0.05) and attenuated vascular remodeling (P<0.05). JQ1 had no effect on mean systemic arterial pressure or heart rate at the doses tested. Furthermore, pro-inflammatory cytokines including IL-6 and IL-8 were significantly reduced in serum from JQ1-treated mice compared to hypoxia/SU5416 control (Table I). Consistent with this, JQ1 significantly attenuated the synthetic PASMC phenotype, significantly reducing IL-6 and MCP-1 secretion (P<0.001), as well as enhanced type-I collagen and CTGF expression.

Conclusion: This data supports a key role for BET bromodomain proteins in the pathological switching of PASMCs.  Consistent with this, JQ1 inhibited vascular remodeling and the development of PAH in the hypoxia/Su5416 mouse model of PAH. Suggesting targeting of bromodomain proteins may represent a novel therapeutic approach to targeting SSc-PAH.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bromodomain-inhibitor-jq1-modulates-smooth-muscle-cell-switching-and-ameliorates-chronic-hypoxiasu5416-induced-pulmonary-arterial-hypertension-in-mice/