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Aug 26, 2010
 |  BC Innovations  |  Targets & Mechanisms

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 vascular remodeling that characterizes the disease.

The group's new study not only supports the rationale for targeting PDK but also highlights additional targets in the pathway that could be explored for PAH "Targeting pulmonary hypertension through metabolic pathways").see Figure 1, "Targeting pulmonary hypertension through metabolic pathways").

PDK inhibition is known to reduce pyruvate dehydrogenase (PDH), a key enzyme that promotes glucose oxidation.

Increased fatty acid oxidation is also known to inhibit PDH. Thus, the researchers reasoned that reducing fatty acid oxidation could be expected to activate PDH and increase glucose oxidation.

The team selected malonyl-CoA decarboxylase (MLYCD; MCD) as a candidate target because it is a key regulatory enzyme needed for fatty acid oxidation.4 Moreover, MCD inhibition has been shown to decrease fatty acid oxidation, activate PDH and increase glucose oxidation.5

In mice, the Canadian researchers showed thatgenetic knockout of MCD prevented hypoxia-induced PAH and the associated vascular remodeling in pulmonary artery smooth muscle cells. Under hypoxic conditions, the pulmonary artery of mice with functional Mcd showed a shift toward glycolysis and away from glucose oxidation compared with the artery of control mice housed under normoxic conditions. In contrast, the pulmonary...

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