| Summary: | 博士 === 國立陽明大學 === 藥理學研究所 === 107 === Background and Purpose－Cardiovascular disease is the major cause of death in the world. Especially, myocardial and cerebral ischemia-reperfusion (I-R) injury could cause critical disability even life-threatening. Protection and restoration of the functional tissue is an important issue for I-R injury. Growth differentiation factor 11 (GDF11) is the member of transforming growth factor β (TGF-β) superfamily. The previous study showed that GDF11 could reverse age-related cardiac hypertrophy and increase neurogenesis and angiogenesis in the aged mouse. Their data suggest that GDF11 has the ability to maintain adult stem cell in the younger stage. Recently, overexpression of GDF11 gene was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after I-R in aged mice. In addition, systemic GDF11 treatment meliorates vasculature in the hippocampus and cortex of old mice. However, no investigation explored the cardiac and neuronal protective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. Therefore, we would like to investigate whether exogenous recombinant GDF11 protects against acute myocardial I-R injury in rats. Moreover, systemic application of GDF11 cannot cross the brain blood barrier and systemic application of high dose GDF11 was found to have deleterious effects such as erythroid immaturation and severe cachexia. In this study, we further investigated the neuroprotective effect of local application and slowing releasing of GDF11 in mice subjected to focal cerebral I-R injury. In addition, the underlying mechanisms were also revealed in both I-R models.
Methods and Results－This study consists of two main components. (1) Myocardial I-R injury was induced by left anterior descending coronary artery (LAD) occlusion in rats. Pretreatment and post-treatment with 0.1 mg/kg GDF11 reduced arrhythmia and myocardial infarction, increased cardiac systolic and diastolic function, suppressed programmed cell death, inflammation, oxidative stress, and Wnt4 expression. GDF11 activated the canonical pathway of TGF-β, conversely, GDF11 inactivated the non-canonical pathways of TGF-β, ERK and JNK. Our data suggest that exogenous GDF11 has cardioprotective effects, as it reduced the detrimental effect of the TGF-β signaling pathway in the acute stage of I-R injury. In addition, pretreatment with follistatin (FST), the inhibitor of GDF11 and activin subfamily, blocked the activation of Smad2/3 signaling and cardioprotective effects of GDF11. (2) Focal cerebral I-R injury was induced by middle cerebral artery occlusion (MCAO) in mice. In focal cerebral I-R study, the effects of local application and slow-releasing of GDF11 (1 μg/kg) by fibrin glue on focal cerebral I-R injury was investigated. We found that GDF11 improved cerebral infarction and sensorimotor function after cerebral I-R injury via Smad2/3 upregulation but FOXO3 downregulation. Administration with GDF11 reduced the oxidation of protein and lipid as well as the expression of iNOS and COX2, at 24 hr focal cerebral I-R injury. GDF11 not only protected hippocampal neuron and subventricular neural stem cell against I-R injury but also suppressed astrocyte activation. Astonishingly, endothelial cells were whittled down in peri-infarcted site. Furthermore, by systematic profiling, we also found that some mRNA levels associating with neurogenesis were increasing. In addition, GDF11 upregulated more mRNA levels associating with anti-angiogenesis than pro-angiogenesis in GDF11 treated brain.
Conclusions－In this study, we found that pretreatment or treatment with exogenous recombinant GDF11 may assist with morphologic and functional recovery in the early stage of myocardial I-R injury. In addition, local application with slow-releasing of GDF11 on the infarcted brain effectively decreased the damage of I-R injury. GDF11 showed cardioprotective and neuroprotective effects via anti-oxidation, anti-inflammation in both I-R models and pro-neurogenesis in focal cerebral I-R injury. However, we also found GDF11 reduced the vasculature formation near peri-infarcted brain subjected to I-R damage. Therefore, we suggest that the neuroprotective effect of local application with slow-releasing of GDF11 is not through promotion of angiogenesis and improvement of blood perfusion. Our study raises the potential of GDF11 to be a therapeutic approach against myocardial and focal cerebral I-R injury.
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