Mitochondrial Hyperpolarization in Pulmonary Vascular Remodeling. Mitochondrial Uncoupling Protein Deficiency as Disease Model

Abstract

Alterations of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitochondrial respiration are possible triggers of pulmonary vascular remodeling in pulmonary hypertension (PH). We investigated the role of MMP in PH and hypothesized that deletion of the mitochondrial uncoupling protein 2 (UCP2) increases MMP, thus promoting pulmonary vascular remodeling and PH. MMP was measured by JC-1 in isolated pulmonary arterial smooth muscle cells (PASMCs) of patients with PH and animals with PH induced by exposure to monocrotaline (MCT) or chronic hypoxia. PH was quantified in vivo in UCP2-deficient (UCP2(-/-)) mice by hemodynamics, morphometry, and echocardiography. ROS were measured by electron spin resonance spectroscopy and proliferation by thymidine incorporation. Mitochondrial respiration was investigated by high-resolution respirometry. MMP was increased in PASMCs of patients and in animal models of PH. UCP2(-/-) mice exhibited pulmonary vascular remodeling and mild PH compared with wild-type (WT) mice. PASMCs of UCP2(-/-) mice showed increased proliferation, MMP, and ROS release. Increased proliferation of UCP2(-/-) PASMCs could be attenuated by ROS inhibitors and inhibited by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, which decreased MMP to the level of WT mice. Mitochondrial respiration was altered in PASMCs from MCT rats and PASMCs exposed to hypoxia but not in isolated pulmonary mitochondria of UCP2(-/-) mice or PASMCs after treatment with small interfering RNA for UCP2. Our data suggest that increased MMP causes vascular remodeling in UCP2(-/-) mice partially via increased ROS. In chronic hypoxia and MCT-induced PH, additional pathomechanisms such as decreased respiration may play a role.

Do Not Overcharge the System or It Will Explode!

“…Such a mechanism also seems to contribute to the anti-inflammatory activity of UCPs, 7 an aspect also of relevance to the vascular system; transplantation of UCP2 −/− bone marrow into LDLR −/− mice increased atherosclerosis development, 8 and global UCP2 −/− mice exhibited increased inflammatory activity and enhanced aortic macrophage deposition in response to atherogenic diet. 9 In many cell types, including smooth muscle cells and fibroblasts, ROS-stimulated MAP kinase activation promotes proliferation, and therefore it is unlikely that the antiproliferative effect of UCP2 knockout observed in endo thelial cells in the study by Shimasaki et al 4 is universal; for example pulmonary arterial smooth muscle cells harvested from UCP2 −/− mice exhibited accelerated proliferation 10 and increased apoptosis resistance.…”

Emerging Metabolic Therapies in Pulmonary Arterial Hypertension

“…Genetic ablation of UCP2 in PASMCs demonstrated mitochondrial hyperpolarization, decreased activity of calcium-sensitive mitochondrial enzymes, resistance to apoptosis, and established a proliferative phenotype. The same study showed that in vivo knockout of Ucp2 in mice models activated HIF-1α and NFAT, increased remodeling of the pulmonary vasculature, and developed PH [122,123]. In ECs, the loss of UCP2 resulted in exaggerated PTEN-induced putative kinase 1 (Pink1)-induced mitophagy, decreased mitochondrial biosynthesis, and increased apoptosis, indicating that a UCP2-Pink1 axis might serve as a therapeutic target [124].…”

Being right on Q: shaping eukaryotic evolution

“…Is mt hyperpolarization found under more normal circumstances? It occurs in T-cell activation [95,96], is supposed to be a factor in disease complications upon high blood glucose in diabetes [97], has been observed over longer periods of stress in astrocytes [98], is a characteristic of arterial smooth muscle cells in pulmonary hypertension [99], and is a ‘sensitizing feature’ in apoptotic potential of Caco-2 intestinal cells [100]. Neurons tolerant of transient glutamate excitation show significant mt hyperpolarization in response [101], and it is quite common in many types of cancer cells [102,103].…”