Investigating the Effect of Perhexiline and FPER-1 in pulmonary Arterial Hypertension

Keeler, Ross ORCID: 0000-0001-5874-0464 (2024). Investigating the Effect of Perhexiline and FPER-1 in pulmonary Arterial Hypertension. University of Birmingham. M.Sc.

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Abstract

Pulmonay arterial hypertension (PAH) is a vascular remodelling disease whereby proliferation of pulmonary artery smooth muscle cells (PASMCs) is increased. The pathophysiology of the disease is not fully understood, but there is a growing body of evidence in the literature that supports the notion that PAH PASMCs exhibit a similar metabolic phenotype to that of cancer cells. Previous studies have shown that PAH PASMCs reprogram their energy metabolism to utilise glycolysis over oxidative phosphorylation for ATP production due to a reduction in pyruvate dehydrogenase (PDH) activity. In the present study, we hypothesised that by increasing PDH activity, perhexiline and the novel fluorinated perhexiline (FPER-1), both carnitine palmitoyltransferase 1 (CPT1) inhibitors, would restore PDH flux and hence increase oxidative phosphorylation, and attenuate PASMCs proliferation. Utilising cultured PASMCs from healthy and PAH patient donors, we showed that perhexiline and FPER-1 effectively attenuates the increased rate of proliferation of PASMCs from PAH donors, whilst maintaining cell viability. We futher propose a novel mechanism of action of perhexiline/FPER-1 in PAH PASMCs whereby both perhexiline and FPER-1 reduces PAH PASMC proliferation by suppressing the activation of the AKT pathway (reduced phosphorylation of AKTser473) and activating PDH (dephosphorylation of PDH-E1α ser293). Our findings demonstrate that both perhexiline and FPER-1 show promise as a novel therapeutic agent for reversing the increased PASMC proliferation apparent in PAH, but additional studies regarding the safety of FPER-1 as a therapy are required.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):