The Metabolic Theory of Pulmonary Arterial Hypertension

Abstract

A lthough traditionally pulmonary arterial hypertension (PAH) has been described as a disease exclusively of the pulmonary arteries, there is now evidence that PAH involves many other organs (Figure 1). For example, the hearts (right ventricle [RV]) of patients with PAH decompensate and fail at a much faster rate compared with what one would expect extrapolating from the left ventricle, suggesting that there may be mechanisms intrinsic to the RV that promote RV failure in PAH. Even patients with idiopathic PAH, without coexistent autoimmune disorders, have circulating immune cells that are activated, producing a strong inflammatory environment and potentially contributing to the malaise and weakness that patients with PAH have. Recent evidence suggests that, perhaps, their skeletal muscles (the target organs in the metabolic syndrome) have abnormalities similar to patients with diabetes mellitus, obesity, and

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

“…Strikingly, metabolic changes, resembling those observed in cancer, have also recently been reported in PH (1,2,4,6,7). These changes have been described to occur in smooth muscle cells (SMCs) (8), endothelial cells (7), and, recently, in fibroblasts (9).…”

“…However, complex I defects have not yet been described in other cell types involved in the remodeling of the pulmonary artery wall during PH development, such as SMCs and endothelial cells. In these cells, mitochondria were shown to be hyperpolarized, with a restricted influx of carbohydrates, and thus mitochondrial energy metabolism is suppressed and cells are apoptosis resistant (4). Further studies need to be directed at investigating the relevance of complex I disorders in PH.…”

“…The vascular remodeling observed in PH involves an imbalance of cell proliferation versus cell death and, almost uniformly, persistent inflammation. These observations have led to the hypothesis that the cellular and molecular features of PH resemble hallmark characteristics of cancer (1)(2)(3)(4)(5)(6). It is increasingly recognized that changes in cell metabolism in cancer cells, as well as in cells in the surrounding stroma, are essential for cancer cells to proliferate, migrate, and exhibit proinflammatory characteristics.…”

Mitochondrial integrity in a neonatal bovine model of right ventricular dysfunction

“…Mitochondria produce Ͼ95% of cardiac ATP and thus are an important source of energy for the energy-sensitive heart. The potential role of impaired metabolism in PH and RV failure has recently been put forth as one mechanism for cardiac disease progression, spurring a metabolic hypothesis of PH that features a global mitochondrial abnormality and metabolic disturbance (33). Accumulating evidence suggests mitochondrial dysfunction may be involved in HF, and mitochondrial dysfunction may explain the energy deficits associated with the failing heart.…”

Potassium channels in pulmonary arterial hypertension

“…No information is available on the PTM status of K V 1.5 channels in PAH. Taking into account that metabolic pathways provide substrates for PTM and that PAH is recognised as a disorder associated with significant metabolic dysfunction, it can be assumed that major alterations in PTM of K + channels occur in PAH [76,77]. Nonetheless, the likely importance of these regulatory mechanisms remains to be explored.…”