The neonatal mammalian heart has a remarkable regenerative capacity,while the adult heart has difficulty to regenerate.A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of ca...The neonatal mammalian heart has a remarkable regenerative capacity,while the adult heart has difficulty to regenerate.A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth.In this study,we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation.Reversing metabolic reprogramming by carnitine palmitoyltransferase 1(CPT1)inhibition,using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction.The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir,a CPT1 inhibitor.CPT1 inhibition,by decreasing poly(ADP-ribose)polymerase 1 expression,reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes,leading to decreased p38 MAPK phosphorylation,and stimulation of cardiomyocyte proliferation.Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation.CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.展开更多
Myocardial dysfunction is the most serious complication of sepsis.Sepsis-induced myocardial dysfunction(SMD)is often associated with gastrointestinal dysfunction,but its pathophysiological significance remains unclear...Myocardial dysfunction is the most serious complication of sepsis.Sepsis-induced myocardial dysfunction(SMD)is often associated with gastrointestinal dysfunction,but its pathophysiological significance remains unclear.The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD.In mice,knockdown of the gastrin receptor,cholecystokinin B receptor(Cckbr),aggravated lipopolysaccharide(LPS)-induced cardiac dysfunction and increased inflammation in the heart,whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury.Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes,48 h prior to LPS administration,alleviated LPSinduced cardiac injury in Cckbr-deficient mice.The intravenous injection of bone marrow macrophages(BMMs)overexpressing Cckbr reduced LPS-induced myocardial dysfunction.Furthermore,gastrin treatment inhibited toll-like receptor 4(TLR4)expression through the peroxisome proliferator-activated receptor a(PPAR-a)signaling pathway in BMMs.Thus,our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD,which could be used to develop new treatment modalities for SMD.展开更多
基金supported by grants from the National Key Research and Development Program of China(No.2022YFA1104500)National Natural Science Foundation of China(No.81930008)+1 种基金Natural Science Foundation of Sichuan Province(No.2023NSFSC1651,China)the National Institutes of Health(No.DK134574 and No.DK119652,US).
文摘The neonatal mammalian heart has a remarkable regenerative capacity,while the adult heart has difficulty to regenerate.A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth.In this study,we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation.Reversing metabolic reprogramming by carnitine palmitoyltransferase 1(CPT1)inhibition,using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction.The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir,a CPT1 inhibitor.CPT1 inhibition,by decreasing poly(ADP-ribose)polymerase 1 expression,reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes,leading to decreased p38 MAPK phosphorylation,and stimulation of cardiomyocyte proliferation.Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation.CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.
基金supported by grants to Chunyu Zeng from the Program of Innovative Research Team by National Natural Science Foundation(81721001,China)National Natural Science Foundation of China(31430043,31730043)+5 种基金Program for Changjiang Scholars,and Innovative Research Team in University(IRT1216,China)the National Key R&D Program of China(2018YFC1312700)by grant to Jingwen Guo from the National Natural Science Foundation of China(82000476)by grant to Yijie Hu from the Excellent Talents Project of Third Military Medical University(B-3232,China)by grant to Hongyong Wang from the Clinical Technology Innovation and Cultivation Program of AMU(CX2019JS220,China)by grant to Xinyue Li from Chongqing Natural Science Foundation(CSTB2022NSCQ-BHX0025,China)。
文摘Myocardial dysfunction is the most serious complication of sepsis.Sepsis-induced myocardial dysfunction(SMD)is often associated with gastrointestinal dysfunction,but its pathophysiological significance remains unclear.The present study found that patients with SMD had higher plasma gastrin concentrations than those without SMD.In mice,knockdown of the gastrin receptor,cholecystokinin B receptor(Cckbr),aggravated lipopolysaccharide(LPS)-induced cardiac dysfunction and increased inflammation in the heart,whereas the intravenous administration of gastrin ameliorated SMD and cardiac injury.Macrophage infiltration plays a significant role in SMD because depletion of macrophages by the intravenous injection of clodronate liposomes,48 h prior to LPS administration,alleviated LPSinduced cardiac injury in Cckbr-deficient mice.The intravenous injection of bone marrow macrophages(BMMs)overexpressing Cckbr reduced LPS-induced myocardial dysfunction.Furthermore,gastrin treatment inhibited toll-like receptor 4(TLR4)expression through the peroxisome proliferator-activated receptor a(PPAR-a)signaling pathway in BMMs.Thus,our findings provide insights into the mechanism of the protective role of gastrin/CCKBR in SMD,which could be used to develop new treatment modalities for SMD.
