The following is an excellent excerpt from Metabolic Regulation: A Human Perspective, by Keith N. Frayn. After reading it, the connection between metabolism (specifically mitochondrial oxidative metabolism capacity) and PH should be clear. I’ll leave the in depth commentary of why (including how, if this is true, PH is restricted to affecting lungs as opposed to systemic circulation) for another post:

“An important aspect of metabolic regulation and its adaptation to different circumstances is the use of oxygen to oxidize nutrients and, hence, generate ATP. There are two aspects relevant to this chapter. The first is a series of mechanisms that increase the ability of tissues to conduct oxidative metabolism. We noted above that PPAR-alpha increases the expression of genes involved in fatty acid oxidation. PPAR-delta does the same, perhaps with a stronger effect in skeletal muscle. These adaptations will provide more substrate (acetyl-CoA) for oxidation. But the ability of a cell to oxidize acetyl-CoA may be limited by the mitochondrial capacity of that cell: either the number of mitochondria may be inadequate, or the capacity of each mitochondria may be. Studies of the transcriptional co-activator PGC-1alpha have shown that this, and other members of the PGC family, are “master regulators” of mitochondrial capacity. In studies in which PGC-1alpha expression has been experimentally up-regulated, the number of mitochondria in the cell concerned increases, and the expression of oxidative enzymes in those mitochondria will also increase. If PGC-1alpha expression is increased in skeletal muscle, the muscle cells take on more oxidative characteristics. PGC-1alpha expression has also been increased experimentally in fat cells (adipocytes). This tends to transform the phenotype of the adipocyte, from a fat-storing cell to a fat-burning cell, akin to transforming white adipose tissue into brown adipose tissue.

The other aspect of regulation of oxidative capacity concerns the availability of oxygen itself. Oxygen is just as important for the body as are the fuels it will oxidize. It is therefore not surprising that the availability of oxygen can alter gene expression. Chronic reduction in oxygen availability (as would occur at high altitude, for example) leads to upregulation of the expression of many genes relating to oxygen transport and energy metabolism. These include the glycoprotein hormone erythropoietin produced in the kidney, which stimulates erythrocyte (red blood cell) production. The glucose transporters GLUT1 and GLUT3 and enzymes of glycolysis are also upregulated (phosphofructokinase, aldolase, and lactate dehydrogenase; particular isoforms are involved in each case). The process of angiogenesis, formation of new blood vessels, is also stimulated, so that regions of tissue that are not receiving enough oxygen become better perfused. The molecular mechanisms by which this is achieved are outside the scope of this book, but there is an important transcription factor that is activated when oxygen availability is low, known as hypoxia-inducible factor-1 or HIF-1.”

If the connection still isn’t clear, I’ll leave you with the following paper (from the PH literature) to help support my case: The Metabolic Basis of Pulmonary Arterial Hypertension

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