nary arterial hypertension (PAH) is a devastating disease affecting lung vasculature. The pulmonary arteries become occluded due to increased proliferation and suppressed apoptosis of the pulmonary artery smooth muscle cells (PASMCs) within the vascular wall. It was recently shown that DNA damage could trigger this phenotype by upregulating poly(ADP-ribose)polymerase 1 (PARP-1) expression, although the exact mechanism remains unclear. In silico analyses and studies in cancer demonstrated that microRNA miR-223 targets PARP-1. We thus hypothesized that miR-223 downregulation triggers PARP-1 overexpression, as well as the proliferation/apoptosis imbalance observed in PAH. We provide evidence that miR-223 is downregulated in human PAH lungs, distal PAs, and isolated PASMCs. Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1␣, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis. Finally, we demonstrated that restoring the expression of miR-223 in lungs of rats with monocrotaline-induced PAH reversed established PAH and provided beneficial effects on vascular remodeling, pulmonary resistance, right ventricle hypertrophy, and survival. We provide evidence that miR-223 downregulation in PAH plays an important role in numerous pathways implicated in the disease and restoring its expression is able to reverse PAH. miR-223; pulmonary hypertension; PARP-1; HIF-1␣; DNA damage PULMONARY ARTERIAL HYPERTENSION (PAH) is a serious condition characterized by obstruction of the precapillary pulmonary arterioles (PA) due to excessive vasoconstriction, inflammation, and imbalance between cells' proliferation and apoptosis within the arterial wall. This remodeling and obstruction of the PAs leads to increases in pulmonary vascular resistance, right ventricular (RV) failure, and death of patients. Despite recent therapeutic advances, most patients exhibit persistently poor exercise capacity and quality of life, with a 3-yr survival rate of 65% (12).Growing evidence underlines the importance of DNA damage in PAH etiology (9,19,23). Indeed, the sustained inflammation, RAGE expression (21), and metabolic stress (30) observed in PAH result in DNA damage-dependent activation of poly(ADP-ribose)polymerase 1 (PARP-1) in PA smooth muscle cells (PASMCs) of PAH patients (23). We recently showed that PARP-1 overexpression was responsible for enhanced PAH-PASMC proliferation and suppressed apoptosis (23). Nevertheless, the mechanisms that regulate this overexpression in PAH remain elusive.In cancer, PARP-1 expression is regulated by microRNA-223 (miR-223), a microRNA involved in DNA damage response (34). According to TargetScan 6.2, PARP-1 is in fact a predicted target of miR-223. Moreover, downregulation of miR-223 has been shown to mediate mechanical stretch-stimulated proliferation of vascular smooth muscle cells (33). Interestingly, Wang et al. (38) reported that miR-...
Among the causes, modifications of the mitochondrial function could be of major importance. Polyunsaturated fatty (-3) acids have been shown to play a role in intracellular functions. We hypothesize that docosahexaenoic acid (DHA) supplementation could improve muscle mitochondrial function that could contribute to limit the early consequences of aging on adult muscle. Twelve-month-old male Wistar rats were fed a low-polyunsaturated fat diet and were given DHA (DHA group) or placebo (control group) for 9 wk. Rats from the DHA group showed a higher endurance capacity (ϩ56%, P Ͻ 0.05) compared with control animals. Permeabilized myofibers from soleus muscle showed higher O2 consumptions (P Ͻ 0.05) in the DHA group compared with the control group, with glutamate-malate as substrates, both in basal conditions (i.e., state 2) and under maximal conditions (i.e., state 3, using ADP), along with a higher apparent Km for ADP (P Ͻ 0.05). Calcium retention capacity of isolated mitochondria was lower in DHA group compared with the control group (P Ͻ 0.05). Phospho-AMPK/AMPK ratio and PPAR␦ mRNA content were higher in the DHA group compared with the control group (P Ͻ 0.05). Results showed that DHA enhanced endurance capacity in adult animals, a beneficial effect potentially resulting from improvement in mitochondrial function, as suggested by our results on permeabilized fibers. DHA supplementation could be of potential interest for the muscle function in adults and for fighting the decline in exercise tolerance with age that could imply energy-sensing pathway, as suggested by changes in phospho-AMPK/AMPK ratio. polyunsaturated fatty acids; isolated mitochondria; permeabilized myofibers; muscle bioenergetics AGING IS ASSOCIATED WITH A PROGRESSIVE DECREASE in muscle mass and alterations in muscle function leading to reduced physical abilities, exercise performance and quality of life, and ultimately disabilities (21,26,36). Among the causes of such sarcopenia, inadequate protein synthesis matching protein degradations is of major importance (4, 12). Also, changes in metabolism could be part of the muscle mass decrease with age.
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