Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/intervent...Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models,which are not transferable or reproducible in large animal models due to different factors such as:(i)complex and varied features of human ischemic cardiac disease(ICD),which are challenging to mimic in animal models,(ii)significant differences in surgical techniques applied,and(iii)differences in cardiovascular anatomy and physiology between small versus large animals.This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury(IRI),as well as the different methods used to induce and assess IRI,and the obstacles faced in using large animals for translational research in the settings of cardiac IR.展开更多
We have quantified the impacts of anthropogenic emissions reductions caused by the Air Pollution Control Action Plan and changes in meteorological fields between 2013 and 2017 on the warm-season O3 concentration in Ch...We have quantified the impacts of anthropogenic emissions reductions caused by the Air Pollution Control Action Plan and changes in meteorological fields between 2013 and 2017 on the warm-season O3 concentration in China using a regional 3D chemical transport model. We found that the impact on daily maximum eight-hour (MDA8) O3 concentration by the meteorological variation that mostly increased O3 was greater than that from emission reduction, which decreased O3. Specifically, the control measures implemented since 2013 in China have reduced SO2, NOx, PM2.5, and VOC emissions by 33%, 25%, 30%, and 4% in 2017, while NH3 emissions have increased by 7%. The changes in anthropogenic emissions lowered MDA8 O3 by 0.4–3.7 ppb (0.8%–7.6%, varying by region and month), although MDA8 O3 was increased slightly in some urban areas (i.e. North China) at the beginning/end of warm seasons. Relative to 2013, the average 2 m temperature in 2017 shows increments in North, North-east, East, and South China (0.34℃–0.83℃) and decreases in Central China (0.24℃). The average solar radiation shows increments in North, North-east, and South China (7.0–9.7 w/m2) and decreases in Central, South-west, and North-west China (4.7–10.3 w/m2). The meteorological differences significantly change MDA8 O3 by -3.5–8.5 ppb (-8.2%–18.8%) with large temporal variations. The average MDA8 O3 was slightly increased in North, North-east, East, and South China. The response surface model suggests that the O3 formation regime transfers from NOx-saturated in April to NOx-limited in July on average in China.展开更多
Disruption of the mitochondrial quality surveillance(MQS)system contributes to mitochondrial dysfunction in diabetic cardiomyopathy(DCM).In this study,we observed that cardiac expression of phosphoglycerate mutase 5(P...Disruption of the mitochondrial quality surveillance(MQS)system contributes to mitochondrial dysfunction in diabetic cardiomyopathy(DCM).In this study,we observed that cardiac expression of phosphoglycerate mutase 5(PGAM5),a mitochondrial Ser/Thr protein phosphatase,is upregulated in mice with streptozotocin-induced DCM.Notably,DCM-related cardiac structural and functional deficits were negated in cardiomyocyte-specific Pgam5 knockout(Pgam5^(CKO))mice.Hyperglycemic stress impaired adenosine triphosphate production,reduced respiratory activity,and prolonged mitochondrial permeability transition pore opening in acutely isolated neonatal cardiomyocytes from control Pgam5^(f/f) mice,and these effects were markedly prevented in cardiomyocytes from Pgam5^(CKO) mice.Likewise,three main MQS-governed processes—namely,mitochondrial fission/fusion cycling,mitophagy,and biogenesis—were disrupted by hyperglycemia in Pgam5^(f/f),but not in Pgam5^(CKO),cardiomyocytes.On the basis of bioinformatics prediction of interaction between PGAM5 and prohibitin 2(PHB2),an inner mitochondrial membrane-associated scaffolding protein,co-immunoprecipitation,and immunoblot assays demonstrated that PGAM5 dephosphorylates PHB2 on Ser91.Transfection of cardiomyocytes with phosphodefective or phosphomimetic Ser91 mutants of PHB2 confirmed a critical role for PGAM5-mediated dephosphorylation of PHB2 in mitochondrial dysfunction associated with hyperglycemic stress.Furthermore,knockin mice expressing phosphomimetic PHB2^(S91D) were resistant to diabetes-induced cardiac dysfunction.Our findings highlight the PGAM-PHB2 axis as a novel and critical regulator of mitochondrial dysfunction in DCM.展开更多
基金supported by the Early Career Scheme(ECS)2022/23(CUHK 24110822)from the Research Grants Council of Hong Kongthe Direct Grant for Research 2020/21(2020.035)+3 种基金Project Impact Enhancement Fund(PIEF)(PIEF/Ph2/COVID/08)Improvement on Competitiveness in Hiring New Faculties Funding Scheme from CUHK as well as the Centre for Cardiovascular Genomics and Medicine(CCGM)of the Lui Che Woo Institute of Innovative Medicine CUHK(to S.B.O.)a CUHK Department of Medicine&Therapeutics(MEDT)-funded PhD studenta CUHK Vice-Chancellor’s PhD Scholarship holder。
文摘Large animal models of cardiac ischemia-reperfusion are critical for evaluation of the efficacy of cardioprotective interventions prior to clinical translation.Nonetheless,current cardioprotective strategies/interventions formulated in preclinical cardiovascular research are often limited to small animal models,which are not transferable or reproducible in large animal models due to different factors such as:(i)complex and varied features of human ischemic cardiac disease(ICD),which are challenging to mimic in animal models,(ii)significant differences in surgical techniques applied,and(iii)differences in cardiovascular anatomy and physiology between small versus large animals.This article highlights the advantages and disadvantages of different large animal models of preclinical cardiac ischemic reperfusion injury(IRI),as well as the different methods used to induce and assess IRI,and the obstacles faced in using large animals for translational research in the settings of cardiac IR.
基金the National Key R&D Program of China(Nos.2018YFC0213805, 2017YFC0210006)National Natural Science Foundation of China(Grant Nos.21625701 ,51861135102)National Research Program for Key Issues in Air Pollution Control(Nos.DQGG0301 ,DQGG0305).This work was completed on the"Explorer 100"cluster system of Tsinghua National Laboratory for Information Science and Technology.
文摘We have quantified the impacts of anthropogenic emissions reductions caused by the Air Pollution Control Action Plan and changes in meteorological fields between 2013 and 2017 on the warm-season O3 concentration in China using a regional 3D chemical transport model. We found that the impact on daily maximum eight-hour (MDA8) O3 concentration by the meteorological variation that mostly increased O3 was greater than that from emission reduction, which decreased O3. Specifically, the control measures implemented since 2013 in China have reduced SO2, NOx, PM2.5, and VOC emissions by 33%, 25%, 30%, and 4% in 2017, while NH3 emissions have increased by 7%. The changes in anthropogenic emissions lowered MDA8 O3 by 0.4–3.7 ppb (0.8%–7.6%, varying by region and month), although MDA8 O3 was increased slightly in some urban areas (i.e. North China) at the beginning/end of warm seasons. Relative to 2013, the average 2 m temperature in 2017 shows increments in North, North-east, East, and South China (0.34℃–0.83℃) and decreases in Central China (0.24℃). The average solar radiation shows increments in North, North-east, and South China (7.0–9.7 w/m2) and decreases in Central, South-west, and North-west China (4.7–10.3 w/m2). The meteorological differences significantly change MDA8 O3 by -3.5–8.5 ppb (-8.2%–18.8%) with large temporal variations. The average MDA8 O3 was slightly increased in North, North-east, East, and South China. The response surface model suggests that the O3 formation regime transfers from NOx-saturated in April to NOx-limited in July on average in China.
基金the Natural Science Foundation of Guangdong Province,China(grant number 2016A030313792)the Basic and Applied Basic Research Project of Guangzhou University Joint Project(no.202201020605)the National Natural Science Foundation of China(82270279 and 82200296).
文摘Disruption of the mitochondrial quality surveillance(MQS)system contributes to mitochondrial dysfunction in diabetic cardiomyopathy(DCM).In this study,we observed that cardiac expression of phosphoglycerate mutase 5(PGAM5),a mitochondrial Ser/Thr protein phosphatase,is upregulated in mice with streptozotocin-induced DCM.Notably,DCM-related cardiac structural and functional deficits were negated in cardiomyocyte-specific Pgam5 knockout(Pgam5^(CKO))mice.Hyperglycemic stress impaired adenosine triphosphate production,reduced respiratory activity,and prolonged mitochondrial permeability transition pore opening in acutely isolated neonatal cardiomyocytes from control Pgam5^(f/f) mice,and these effects were markedly prevented in cardiomyocytes from Pgam5^(CKO) mice.Likewise,three main MQS-governed processes—namely,mitochondrial fission/fusion cycling,mitophagy,and biogenesis—were disrupted by hyperglycemia in Pgam5^(f/f),but not in Pgam5^(CKO),cardiomyocytes.On the basis of bioinformatics prediction of interaction between PGAM5 and prohibitin 2(PHB2),an inner mitochondrial membrane-associated scaffolding protein,co-immunoprecipitation,and immunoblot assays demonstrated that PGAM5 dephosphorylates PHB2 on Ser91.Transfection of cardiomyocytes with phosphodefective or phosphomimetic Ser91 mutants of PHB2 confirmed a critical role for PGAM5-mediated dephosphorylation of PHB2 in mitochondrial dysfunction associated with hyperglycemic stress.Furthermore,knockin mice expressing phosphomimetic PHB2^(S91D) were resistant to diabetes-induced cardiac dysfunction.Our findings highlight the PGAM-PHB2 axis as a novel and critical regulator of mitochondrial dysfunction in DCM.
