Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling

Abstract

Pulmonary arterial hypertension (PAH) is a lethal disease generally characterized by pulmonary artery remodeling. Mitochondrial metabolic disorders have been implicated as a critical regulator of excessively proliferative- and apoptosis-resistant phenotypes in pulmonary artery smooth muscle cells (PASMCs). Dichloroacetate (DCA) is an emerging drug that targets aerobic glycolysis in tumor cells. Atorvastatin (ATO) is widely used for hyperlipemia in various cardiovascular diseases. Considering that DCA and ATO regulate glucose and lipid metabolism, respectively, we hypothesized that the combination of DCA and ATO could be a potential treatment for PAH. A notable decrease in the right ventricular systolic pressure accompanied by reduced right heart hypertrophy was observed in the DCA/ATO combination treatment group compared with the monocrotaline treatment group. The DCA/ATO combination treatment alleviated vascular remodeling, thereby suppressing excessive PASMC proliferation and macrophage infiltration. In vitro, both DCA and ATO alone reduced PASMC viability by upregulating oxidative stress and lowering mitochondrial membrane potential. Surprisingly, when combined, DCA/ATO was able to decrease the levels of reactive oxygen species and cell apoptosis without compromising PASMC proliferation. Furthermore, suppression of the p38 pathway through the specific inhibitor SB203580 attenuated cell death and oxidative stress at a level consistent with that of DCA/ATO combination treatment. These observations suggested a complementary effect of DCA and ATO on rescuing PASMCs from a PAH phenotype through p38 activation via the regulation of mitochondrial-related cell death and oxidative stress. DCA in combination with ATO may represent a novel therapeutic strategy for PAH treatment.

Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation

“…We further found that the level of the macrophage biomarker CD68 was reduced in the lung tissue of MCT-induced rats after DON treatment, indicating reduced pulmonary macrophage infiltration in DON group rats. This is consistent with the findings of previous studies, in which extensive infiltration of macrophages around the pulmonary perivascular region was observed in various animal models ( 45 , 46 ). More importantly, the findings suggested that M2-macrophage activation plays a more predominant role in PAH development than M1-macrophage activation via regulation of profibrotic and proinflammatory effects ( 11 ).…”

Antitumor Therapy under Hypoxic Microenvironment by the Combination of 2-Methoxyestradiol and Sodium Dichloroacetate on Human Non-Small-Cell Lung Cancer

“…The typical example is “the Warburg effect” or aerobic glycolysis. Glucose consumption and lactate production induced by hypoxia or by the Warburg effect are reversed by DCA, and these results agree with several studies [ 18 , 19 ]. In addition, a decrease in lactate production also reduces acidosis, which is involved in tumor progression [ 20 ].…”

Dan-Shen-Yin Granules Prevent Hypoxia-Induced Pulmonary Hypertension via STAT3/HIF-1α/VEGF and FAK/AKT Signaling Pathways

“…The pathological mechanism of HPH is very complicated. Consistent with network analysis, previous studies have demonstrated that the development of pulmonary hypertension is highly related to oxidative stress ( Mikhael et al, 2019 ; Li et al, 2020 ; Türck et al, 2020 ). Our preliminary experiments show that DSY has no effect on PH induced by monocrotaline (results are not shown), but is effective for HPH.…”