![]() ![]() Our studies demonstrate a critical role for Ucp2 in preventing excessive EC apoptosis and mitophagy that lead to IH-induced PH and right heart dysfunction. EC apoptosis is thought represent the initial pathological presentation of PH but the early molecular events associated with EC apoptosis in PH are not well defined ( 23). However, little is known about Ucp2 in endothelial cells (EC), which also play a key role in PH pathogenesis. ![]() Recently, Ucp2 knockout mice were found to have worse hypoxia-induced PH and the authors attributed the mechanism to cellular dysfunction in PASMC, such as endoplasmic reticulum stress, mitochondrial calcium influx imbalance and mitochondrial hyperpolarization ( 21, 22). Ucp2 has been studied primarily in central nervous system and pancreas, where its role was established in neurotransmission, synaptic plasticity and neurodegenerative processes ( 19) as well as in insulin resistance ( 20). Ucp2 is widely expressed in central nervous system, pancreas, liver and lungs and known to regulate fatty acid metabolism ( 15), mitochondrial calcium uptake ( 16) and mitochondrial reactive oxygen species production ( 16- 18). Ucp1, known as thermogenin, is expressed in brown adipose tissue and dissipates the proton gradient into heat ( 14). Thus far 5 Ucp family members have been discovered ( 13). ![]() Ucp2 belongs to a family of anion transporters that are localized on inner mitochondrial membrane and dissipate proton gradient originated from mitochondrial electron transport chain ( 12). We selected IH as a model of oxidant-induced vascular injury, which is thought to be a common mechanism underlying PH-associated disorders, such as parenchymal lung disease, obstructive sleep apnea and heart failure, as well as idiopathic pulmonary arterial hypertension (PAH) ( 9- 11). There are a number of different rodent models for PH, both genetic and pharmacological ( 6, 7), including intermittent hypoxia (IH) ( 8). Recently, the role of the mitochondria in altering PASMC and pulmonary artery endothelial cells to an apoptosis-resistant phenotype has gained attention ( 3- 5). Dysregulated angiogenesis ( 1), growth factor induction and pulmonary smooth muscle cell (PASMC) apoptosis resistance ( 2) have been invoked as important pathogenetic mechanisms. ![]() Therapies as well as our molecular understanding of PH remain limited. Pulmonary hypertension (PH) is a progressive and incurable disorder associated with the remodeling of lung vessels, with subsequent right heart failure and early death. ![]()
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January 2023
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