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Metabolic origins for pulmonary hypertension

Researchers at the University of Alberta and Metabolic Modulators Research Ltd. have shown that a pathological shift toward glycolysis could be responsible for the deleterious vascular remodeling seen in pulmonary arterial hypertension.1 The findings highlight key molecules in well-known metabolic pathways that could be targeted to prevent and treat the root cause of the disease as opposed to just its symptoms.

The vascular remodeling seen in PAH is caused by greater proliferation and resistance to apoptosis in vascular cells. This remodeling is typically limited to pulmonary vascular tissues and leads to obstruction of the pulmonary arterial lumen, right ventricular failure and eventual death. Systemic vascular tissues usually remain normal.

Earlier studies from the Alberta group and MMRL-affiliated researchers showed that use of dichloroacetate (DCA) to shift cellular metabolism toward glucose oxidation and away from glycolysis could reverse PAH in rats by reducing cell proliferation and promoting apoptosis in the pulmonary issue.2,3 DCA is a small molecule pyruvate dehydrogenase kinase (PDK) inhibitor.

However, despite the pharmacological data highlighting the potential therapeutic benefits of PDK inhibition and DCA in PAH, the researchers lacked the molecular and genetic evidence to prove that a pathological shift toward glycolysis is indeed responsible for the

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