Tuberous sclerosis complex 2 may be a novel target in pulmonary arterial hypertension therapy

The tumour-supressing protein tuberous sclerosis complex 2 (TSC2) may play a role in preventing or treating pulmonary arterial hypertension (PAH). A deficiency of TSC2 leads through a cascade of biomolecules to thickening and stiffening of pulmonary blood vessel walls, resulting in PAH [1].

The study, presented by Dr Yuanjun Shen (University of Pittsburgh Medical Center, USA), focused on the cell signalling mechanisms regulating cell energy metabolism, proliferation, motility, and survival, and how it relates to the pathogenesis of PAH, a rare life-threatening disease characterised by a progressive increase in pulmonary arterial pressure. A key role is played by the mammalian target of rapamycin (mTOR) as well as other signalling networks in pulmonary vascular cell behaviour, remodelling, and PAH. Dr Shen investigated cell signalling to gain insight into the role of TSC2 in PAH.

Immunohistochemistry showed downregulation of TSC2 in small remodelled pulmonary arteries and isolated pulmonary arterial vascular smooth muscle cells (PAVSMC) obtained from patients with PAH. Pharmacological inhibition of kinases Akt or AMPK suppressed mTORC1-S6 but did not restore TSC2 in dysfunctional human PAH cells. This suggests that other molecular mechanisms may be involved. A next step was to analyse factors promoting pulmonary hypertension. Cell culturing on stiff substrates strongly reduced TSC2 protein in healthy human PAVSMC, which was related to increased cell growth. Increased cell growth was also prevented by re-expression of TSC2. Interestingly, TSC2 deficiency enhanced other signalling molecules (i.e. mTORC1-S6 and YAP/Taz, mTORC2-Akt); thereby increasing PAVSMC proliferation and protection from programmed cell death (apoptosis). Additionally, TSC2 deficiency increased deposits of fibronectin and collagen1A1 in PAVSMC from PAH patients. Growth of healthy PAVSMC on matrices also led to upregulation of key signalling molecules playing a role in increased proliferation. Restoration of TSC2 protein levels by activator protein (SRT2104) reduced collagen and fibronectin levels, inhibited specific TORC proteins (mTORC2-Akt, mTORC1-S6), and, consequently, suppressed cell proliferation. Simultaneously apoptosis was induced in human PAVSMCs.

Based on these results, Dr Shen et al. concluded that TSC2 acts as a mechanosensor and mechanotransducer. The restoration of TSC2 may be considered as a new potentially attractive therapeutic strategy to reverse pulmonary vascular remodelling and overall pulmonary hypertension.

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   1. Shen Y, et al. A97, ATS 2019, 17-22 May, Dallas, Texas, USA.

Posted on 23 July, 201924 March, 2021