| Background:The prevalence of diabetes is increasing rapidly during the last three decades and is now considered as an epidemic worldwide.Cardiovascular complications are believed to be the leading causes of disability and death among diabetic patients,particularly for diabetic cardiomyopathy(DCM).The incidence of heart failure in diabetic patients is more than 2 times higher than that in non-diabetic population.DCM,as a severe complication of diabetes,is mainly characterized by cardiac structure and function disorders,including metabolic dysregulation,left ventricular dysfunction,and cardiomyocyte deterioration.Many diabetic patients suffer cardiac dysfunction,with no obvious coronary artery disease,valvular disease,and cardiovascular risk factors such as hypertension,dyslipidemia,etc.The most important pathological changes of diabetic cardiomyopathy include myocardial interstitial fibrosis,cardiomyocyte apoptosis,cardiomyocyte hypertrophy,as well as lipid and glycogen deposition.Regan et.al found that the occurance and development of diabetic cardiomyopathy is mainly related to interstitial lesions.The pathogenesis of DCM is multifactorial and interstitial fibrosis is one of the most prominent changes in DCM.However,the molecular and cellular mechanisms of cardiac fibrosis in DCM still need to be delineated.At present,the renin-angiotensin-aldosterone system(RAS),myocyte metabolic regulation imbalance,autophagy,calcium metabolic disorder and oxidative stress are considered to be involved in cardiac fibrosis and DCM.Among them,RAS might be the most important which deserves further research.RAS is a complex and variable regulation system,and mechanism of RAS is complicated.Angiotensin-converting enzyme inhibitors(ACEIs),angiotensin receptor blockers(ARBs),and aldosterone antagonists can significantly improve cardiac remodeling and myocardial interstitial fibrosis in patients with heart failure.However,there are still many problems that have not been solved:Angiotensin II production with the help of the chymase pathway cannot be blocked by ACEIs,and intracellular angiotensin II cannot be blocked by ARBs.In recent years,the roles and mechanisms of new RAS members in the treatment of heart failure have been explored.These new members include angiotensin-converting enzyme 2(ACE2),angiotensin 1-7(Ang 1-7),Mas receptor(MasR),angiotensin 1-9(Ang 1-9),angiotensin IV(Ang IV),etc.Without the axis of ACE-Ang?-ATIR,a new axis of ACE2-Ang 1-7-MasR/AT2R is proposed.ACE2 is an important negative regulator of local RAS activation in the heart.It generates Ang-(1-7)by cleavage of Ang I and Ang II and negatively regulates the RAS activation.Our research group found that ACE2 significantly improved myocardial interstitial fibrosis,inhibited cardiac hypertrophy,and improved cardiac remodeling.Both ACE2 overexpression and exogenous Ang-(1-7)protected the heart from Ang II/diabetes-induced cardiac hypertrophy and fibrosis.However,ACE2 is an enzyme containing 805 amino acids,and it is not very stable and is easily degraded in vivo,which also limits its clinical application.A disintegrin and metalloproteinase 17(ADAM 17),also known as tumor necrosis factor alpha converting enzyme(TACE),is widely present in a variety of tissues and cells,particularly in the myocardium,kidney,and brain.Substrates of ADAM 17 were found increasely year by year.At present,more than 80 substrates of ADAM17 have been reported,mainly participating in various physiological and pathological processes such as inflammation,oxidative stress and cell proliferation.Some research groups reported that ADAM17 might be a "molecular switch" that controled inflammation and tissue regeneration.In recent years,several studies have shown that ADAM 17 also plays an important role in organ interstitial fibrosis.The expression of ADAM17 is elevated in the myocardium of patients with dilated cardiomyopathy,and down-regulation of ADAM 17 expression can prevent cardiac hypertrophy and myocardial interstitial fibrosis induced by Ang?.ADAM 17 cleaves ACE2 on the cell membrane,and the cleavage extracellular domain is divided into larger(-80KDa)and smaller(-70KDa)parts,which have similar effects to ACE2 enzyme.Our recent study found that dickkopf-3(DKK3)overexpression substantially alleviated Ang II infusion-induced cardiac hypertrophy and fibrosis by regulating ADAM17/ACE2 pathway activity.However,the role of ADAM17 in DCM is still unclear.Objective:1.To investigate the effect and mechanisms of ADAM17 on cardiac dysfunction and myocardial fibrosis in DCM mice by ADAM17 interference and adenoviral carrier with ADAM17 cDNA.2.To investigate the regulation of ADAM17 on ACE2,AT1R,AT2R and MasR expression in DCM mice3.To investigate the regulation of ADAM17 on ACE2,AT1R,AT2R and MasR expression under high glucose condition In vitro.4.To investigate the effect and mechanisms of ADAM17 on the differentiation of myofibroblasts In vivo and In vitro.Methods:1.Induction of type 1 diabetes in mice and intervention.C57BL/6J male mice were randomly assigned to the following 5 groups(n = 10 per group):normal control(NC),diabetes mellitus(DM),DM+adenovirus vector,DM+ADAM17-shRNA,and DM+Ad-ADAM17.At 8 weeks of age,diabetes was induced by intraperitoneal injections of streptozotocin(STZ)at a dosage of 55 mg/kg body weight for five consecutive days,and non-diabetic mice received injections of equivalent volume of citrate buffer vehicle.One week after STZ administration,fasting blood glucose was measured in tail vein blood samples using a glucometer.Mice with blood glucose levels?16.7 mM were considered as diabetes.To knockdown or increase ADAM17 expression,5×109 UT/200 uL adenovirus-mediated scrambled sequence(Vector),adenovirus-mediated shRNA(ADAM17 shRNA)and adenovirus-mediated ADAM17 cDNA(Ad-ADAM17)was injected into the tail vein.At 20 weeks after diabetes induction,mice were sacrificed.Serum,heart,kidney,liver,intestine and other tissue samples were preserved.2.Measurement of cardiac function.After anesthetizing the mice with isoflurane gas,the left ventricular systolic and diastolic function of the mice was evaluated non-invasively by transthoracic echocardiography using a Vevo 2100 imaging system(VisualSonics,Toronto,Canada).3.Histological and imunohistochemical staining.Hearts were fixed overnight in 4%paraformaldehyde.The tissues were dehydrated and embedded into the corresponding wax blocks,and paraffin sections(thickness:4 ?m)were prepared for subsequent experiments.H&E staining was used to observe the size,morphology and arrangement of cardiomyocytes.Masson trichrome method was used to detect myocardial interstitial fibrosis.Immunohistochemistry was used to detect the expression and distribution of ADAM17 and ACE2 in cardiac tissues.4.Extraction of mouse primary cardiac fibroblasts(CFs).Hearts of newly-born 1-3 days old mice were used to extract CFs by enzymatic digestion.DMEM with 10%fetal bovine serum(FBS)was used to culture it at 37? and 5%CO2.5.Cell culture and design.CFs were cultured in low-glucose DMEM containing 10%FBS at 37? and 5%CO2 till cell fusion of 60%.To investigate the effects of ADAM17 on fibroblast function and signaling pathway under high glucose,we divided CFs into 6 groups:normal control group(NC),hypertonic group(HO),high glucose group(HG),high glucose+empty vector group(HG +Vector),high glucose+ADAM17 gene interference group(HG+ADAM17-shRNA),and high glucose+ADAM17 gene overexpression group(HG+Ad-ADAM 1 7).6.Quantitative real-time RT-PCR.Total RNA was extracted.Applied Biosystems cDNA Reverse Transcription and CWBIO SYBR RT-PCR kits were used for quantitative real-time RT-PCR to explore ADAM17 and ACE2 mRNA levels.7.ADAM 17 activity assay.ADAM17 activity was measured in triplicate for each sample by using the SensoLyte 520 TACE(a-Secretase)Activity Assay Kit(AnaSpec,Fremont,CA).8.Enzyme-linked immunosorbent assay(ELISA).The levels of ACE2,in serums and cell mediums were detected by ELISA.9.Immunofluorescence staining.Primary CFs were used to measure the expression of S100A4 and a-SMA by immunofluorescence staining,and the transformation to myofibroblasts was observed.10.Western blot analysis.We measured the protein expression levels of collagen ?,collagen ?,TGF-?1,ADAM17,ACE2;AT1R,AT2R,MasR,a-SMA,p-p38,p38,p-Smad3,and Smad3 in CFs and tissue protein lysates.GAPDH,?-tubulin and ?-actin were used to loading controls.Results:1.Diabetes in mice leads to myocardial fibrosis,apoptosis and cardiac dysfunction.Diabetes was induced in mice of 8 weeks old by intraperitoneal injection of STZ.Cardiac function,myocardial fibrosis were observed after 20 weeks.Diabetes significantly aggravated myocardial fibrosis.After 20 weeks,the left ventricular diastolic and systolic functions of the mice were examined.Compared with the control group,the left ventricular diastolic and systolic functions in diabetic mice were significantly reduced.2.ADAM17 inhibition can improve cardiac function in DCM.Diabetes was induced by STZ in 8-week-old male C57 mice.After 20 weeks of diabetes,left ventricular ejection fraction(LVEF),fractional shortening(FS),the ratio of early mitral valve velocity(E/A)and early to late diastolic peak annular velocity(E'/A')were examined.Compared with the diabetic mice,ADAM17 inhibition improved LVEF,FS,E/A and E'/A' in diabetic mice.3.ADAM17 inhibition improves myocardial interstitial fibrosis in diabetic mice.One week after STZ injection,fasting blood glucose concentration was markedly elevated in all diabetic groups.At the end of the experiment,blood glucose was significantly increased and body weight was significantly decreased in all diabetic groups when compared with the normal control group.However,neither ADAM17 shRNA nor overexpression altered them.Heart-to-body weight ratio was increased in diabetic mice and decreased by ADAM17-shRNA treatment.Masson's trichrome staining demonstrated that fibrotic area was increased in diabetic hearts as compared with that in normal controls,and ADAM17-shRNA treatment reduced the fibrotic area in comparison with scramble vector treatment.Furthermore,diabetic hearts exhibited higher protein expressions of collagen I and III when compared with normal controls,and ADAM17-shRNA transfection significantly reduced them as compared with scramble vector.4.ADAM 17 can affect the RAS system by sheding ACE2.In vivo,we found that the expression level of ADAM17 in diabetic hearts was significantly increased.ADAM 17 inhibition significantly increased the expression of ACE2 in diabetic hearts and significantly reduced AT1R protein level in diabetic hearts.However,there was no change in the levels of AT2R and MasR proteins.In vitro,the expression and activity of ADAM 17 in CFs were significantly increased under high glucose,and the level of ACE2 mRNA was significantly increased under the stimulation of high glucose,but the protein level did not change.Moreover,the level of ACE2 in the supernatant of the cells was significantly increased,suggesting that the increase of ADAM 17 activity and sheding of ACE2 under high glucose.ADAM17 inhibition effectively increased ACE2 and Ang-(1-7)levels in CFs.5.ADAM 17 inhibition can inhibit myofibroblast transdifferentiation.In vitro,high glucose increased the proportion of myofibroblasts in fibroblasts,whereas ADAM17 inhibition significantly reduced this ratio.When compared with the HG group,ADAM17-siRNA significantly reduced the expression of a-SMA under HG.6.Study on the signal pathway of myofibroblast transdifferentiationWhen compared with the control group,the TGF-p 1/Smad3 pathway was activated under high glucose in CFs,and ADAM17 inhibition could effectively inhibit the activation of TGF-p 1/Smad3 pathway,but not through p38-MAPK signal pathway.Conclusions:1.The expression of ADAM17 is significantly elevated in the heart tissues of diabetic mice.2.ADAM17 inhibition can significantly alleviate myocardial interstitial fibrosis and cardiac dysfunction in DCM mice.3.In vivo and in vitro,ADAM17 inhibition regulates RAS system by shedding ACE2.4.Myofibroblasts transformation was increased under high glucose stimulation.ADAM17 inhibition could reduce the transformation of CFs to myofibroblasts.5.ADAM17 affects myofibroblast transdifferentiation in the DCM model via the TGF-?1/Smad3 pathway.ADAM17 inhibition may protect against cardiac fibrosis and left ventricular dysfunction in diabetic status via downregulation of TGF-?1/Smad3 signaling pathway.1 BackgroundWith the rapid increase in the prevalence of diabetes mellitus(DM)and obesity,more attention is being paid to diabetic complications.Diabetic cardiomyopathy(DCM)is one of the major causes of death in diabetic patients.Obese and diabetic patients show cardiac systolic and diastolic dysfunction without hypertension and coronary artery disease.DCM is characterized by early impairment in diastolic function,with or without concurrent systolic dysfunction,accompanied by the development of cardiomyocyte hypertrophy,myocardial fibrosis and cardiomyocyte apoptosis.A natural competition between glucose and fatty acid metabolism in the heart is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes.Metabolic disorders in DCM precede heart failure.Hyperglycemia and fatty acid overutilization are of enormous significance in DCM;both lead to a condition called "glucolipotoxicity".Recent studies showed that sustained glucolipotoxicity exacerbates inflammation,endoplasmic reticulum stress and apoptosis,impairs proteasomal-mediated protein degradation,and causes misfolded protein accumulation and energy insufficiency.Known to us,AMPK plays a vital role in regulating metabolism,and its activation is beneficial for the treatment of several metabolic diseases,including DCM.AMPK activation can also induce transcription factor EB(TFEB)nuclear translocation and autophagy.TFEB,an important regulator of lysosomal biogenesis,controls the expressions of numerous lysosomal genes and also binds to the promoters and regulates the expression of numerous genes involved in lysosomal-related processes including lysosomal exocytosis,phagocytosis,endocytosis,and autophagy.In a murine model of type II diabetes,cardiomyocyte autophagy was impaired at the level of autophagosome formation or autophagosome-lysosome fusion,depending on the cause of diabetes,disease duration,and severity.Autophagic flux was also severely impaired in the heart of mice fed a Western diet(45%of calories from fat).In addition,lipid overload affects chaperone-mediated autophagy by interfering with lysosome-associated membrane protein type 2A(LAMP2A).Notably,humans and mice with loss of function LAMP2A exhibit impaired autophagosome clearance,lysosomal dysfunction and cardiomyopathy,suggesting that lysosomal autophagy is critical for cardiac remodeling.A disintegrin and metalloprotease protein-17(ADAM17)is an important biological regulator of the cellular microenvironment that sheds numerous cytokines and their receptors.ADAM17 has more than 80 substrates and plays a vital role in multiple cellular process.Angiotensin-converting enzyme 2(ACE2)as one of the ADAM17 substrates,can inhibit the renin-angiotensin system(RAS)and be beneficial for heart failure.ACE2 catalyzes the vasoconstrictive,proinflammatory,and fibrogenic Ang?peptide into the vasodilatory,anti-inflammatory,and antifibrogenic angiotensin-(1-7)peptide.Our previous experiments found that the expression and activity of ADAM17 was significantly increased in DCM myocardium.ADAM17 inhitition can improve cardiac function and myocardial interstitial fibrosis effectively in DCM mice.Adult murine heart is mainly composed of cardiomyocytes and fibroblasts.In adult murine hearts,cardiomyocytes account for 56%and fibroblasts account for 27%.We have clarified the role of ADAM17 in cardiofibroblasts in Part ? experiments.To further study the specific roles of ADAM17 in cardiomyocytes in DCM,we established cardiomyocyte-specific ADAM17 knockout mice(A17?-MHCKD).Objectives1.To investigate the effects of ADAM17 on cardiac function and myocardial remodeling in DCM by cardiomyocyte-specific ADAM 17 knockout mice.2.To investigate the overall genetic changes induced by knocking out ADAM 17 in cardiomyocytes of DCM mice by RNA-Seq.3.To explore the mechanisms of ADAM17 affecting cardiac function and cardiomyocyte autophagy in DCM miceMethods1.Establishing cardiomyocyte-specific ADAM17 knockout mice.Purchase of cardiomyocyte-specific Cre mice:a-MHC-cre;ADAM17 conditional knockout mice:ADAM17fl/fl.The two types of mice were matched and the mice were genotyped to identify ADAM17 cardiomyocyte-specific knockout mice,and the efficiency of myocardial knockout of ADAM17 was verified.2.Mice and study design.Male ADAM17fl/fl mice were given a high-fat diet(45%fat and 0.25%cholesterol).After the mice had abnormal glucose tolerance,a large dose of streptozotocin(STZ;75 mg/kg)was intraperitoneally injected.When fasting blood sugar was greater than 11.1 mmol/L,murine models with type 2 diabetes were successfully established.Experimental mice were divided into ADAM17fl/fl normal control group(Control),ADAM17fl/fl diabetic group(DM),and cardiomyocyte-specific ADAM17 knockout diabetic mice group(A17?-MHCKD DM).Mice were euthanized at the end of 16 weeks after induction of DM,and blood and tissue samples were preserved.3.Cardiac function assessment.Left ventricular systolic and diastolic functions were measured non-invasively by transthoracic echocardiography in anesthetized mice(isoflurane)by using the Vevo2100 imaging system(VisualSonics,Toronto,Canada).The derived echocardiography parameters included Left ventricular end-diastolic diameter(LVEDD),left ventricular ejection fraction(LVEF),fractional shortening(FS),early to late left ventricular filling velocity(E/A)and early to late diastolic peak annular velocity(E'/A').4.Cell culture.H9C2 cardiomyocytes were purchased from ATCC(number:CRL-1446),and cultured in DMEM medium with 10%fetal bovine serum and high glucose at 37?,5%carbon dioxide and 95%relative humidity environment.5.Small interfering RNA(siRNA)transfection.When H9C2 cardiomyocyte fusion reached at 60%,ADAM17-siRNA or negative-siRNA was transfected into cells by Lipofectamine RNA-iMAX,and after 12 hours,it was replaced with DMEM medium containing 10%fetal bovine serum stimulated by the addition of 33.3 mM glucose and 0.4 mM palmitate.The groups were divided as follows:blank control group(Control),glucose/palmitate group(GP),glucose/palmitate+negative control-siRNA group(GP+NC-siRNA),glucose/palmitate+ADAM17-siRNA group(GP+ADAM17-siRNA).6.Quantitative real-time RT-PCR.Total RNA was extracted from freshly isolated murine heart samples by using TRIzol Reagent(Invitrogen,Carlsbad,CA).Applied Biosystems cDNA Reverse Transcription and Takara SYBR RT-PCR kits were used for quantitative real-time RT-PCR.Quantitative values were obtained by using the threshold cycle value(Ct)and relative mRNA expression levels were analyzed by the 2-??Ct method.7.Western blot analysis.Protein extracts were separated by SDS-PAGE and transferred to polyvinylidene fluoride membranes for incubation with primary antibodies for ADAM17,LC3B,Beclinl,LAMP2A,Bcl2,Bax,AMPK,p-AMPK,SQSTM1/p62,cleaved caspase3 and TFEB.Protein levels were normalized to that of ?-actin or GAPDH.8.Histological and immunohistochemical staining.Freshly excised hearts were arrested in diastole,fixed in 4%paraformaldehyde,paraffin-embedded and sectioned(4 ?m)for analyses.Masson's trichrome staining was used to detect fibrosis.Hematoxylin and eosin(H&E)staining was used to show cardiomyocyte morphology.The results were analyzed by using Image-Pro Plus 6.0 software.9.Immunofluorescence staining.H9C2 cardiomyocytes were cultured on 12-well glass slides.The expression position and level of TFEB were detected by immunofluorescence staining,and the nuclei were counterstained using DAPI.Photographing was performed using a laser confocal microscope.10.mRNA expression sequence analysis(RNA-seq).Mouse heart tissue samples from A17?-MHCKD DM and DM group were frozen in liquid nitrogen and sent to Beijing Nuohe Zhiyuan Bioinformatics Co.,Ltd.for total RNA isolation,mRNA purification,library preparation and sequencing.11.GFP-RFP-LC3B kit.H9C2 cardiomyocytes were transfected with GFP-RFP-LC3B Premo autophagy tandem virus tool for 24 hours,then ADAM17-siRNA and NC-siRNA were transfected into H9C2 for 24 hours,and then H9C2 cardiomyocytes were under GP condition for 17 hours.The nuclei were counterstained with DAPI,and the expressions of EGFP and TagRFP were observed by fluorescence microscope.12.Blood lipid testThe contents of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C)and high density lipoprotein cholesterol(HDL-C)in the serums of mice were detected by an automatic biochemical analyzer.13.ADAM17 activity assay.The activity of mouse myocardial tissues and H9C2 cardiomyocytes were measured by SensoLyte 520 TACE(?-Secretase)activity assay kit,and each sample was repeatedly measured.14.TUNEL assay.Apoptosis was detected by using a commercial DNA-fragmentation detection kit(Roche)according to the manufacturer's instructions.15.Enzyme linked immunosorbent assay(ELISA)The expressions of ACE2,MCP1 TNF-and il-6in serum were detected by ELISA.Results1.The expression of ADAM17 was significantly increased in the hearts of DCM mice.The mRNA and protein levels of ADAM17 in DCM myocardium were significantly increased,Western blot and immunohistochemistry shows the activity of ADAM17 was increased.2.Specific knockout of ADAM17 in cardiomyocytes improved cardiac function in DCM mice.Specific knockout of ADAM17 in DCM mice were induced by Cre/loxp system.Compared with ADAM17fl/fl DM mice,the left ventricular systolic and diastolic function can effectively improved in A17a-MHCKD DM mice.3.Cardiomyocyte-specific ADAM17 knockout in DCM improved myocardial interstitial fibrosis and cardiomyocyte apoptosis.Cardiac interstitial fibrosis and cardiomyocyte apoptosis were significantly increased in DCM mice.Compared with ADAM17fl/fl DM mice,the extent of fibrosis and the apoptotic ratio were both effectively reduced in A17?-MHCKD DM mice.4.ADAM17 cleaved ACE2 from cell membrane in cardiomyocytes.In vivo,our results showed that compared with ADAM17fl/fl DM mice,the expression of ACE2 protein was significantly increased in the heart of cardiomyocyte-specific ADAM17 knockout DM mice.In vitro,high glucose and lipid led to elevated ACE2 mRNA level in H9C2,increased activity of ADAM17,and increased level of ACE2 in the medium,but the level of ACE2 protein in cardiomyocytes did not increase,suggesting that high glucose and lipid increased ADAM17 activity and increased its ability to cleave ACE2.ACE2 shedding caused by GP treatment was effectively inhibited,and ACE2 protein level in cells was significantly increased under ADAM17-siRNA treatment.5.Gene expression analysis of mouse heart tissues.The cardiac tissues of both ADAM17fl/fl DM and A17a-MHCKD DM mice were selected for RNA-seq analysis.In the A17?-MHCKD DM heart,217 genes were up-regulated and 440 genes were down-regulated.The differential genes are mainly involved in the biological processes of oxidative phosphorylation,fatty acid degradation,myocardial contraction,fatty acid metabolism and AMPK signaling pathway6.In the DCM model,cardiomyocyte-specific ADAM17 knockout activated the AMPK signaling pathway.Compared with the normal control group,AMPK activity in myocardial tissues was decreased in the DM group.Compared with the ADAM17fl/fl DM group,AMPK was significantly activated in A17a MHCKD DM mice.Myocardial ADAM17 inhibition activated the AMPK signaling pathway in DM mice7.High glucose/palmitic acid(GP)decreased the expressions of TFEB and autophagy-related proteins in H9C2 cardiomyocytes.Compared with control group,the expressions of TFEB and LAMP-2A proteins and LC3?/? ratio in H9C2 were significantly decreased,and p62 level was significantly increased under GP.8.ADAM17 gene interference increased TFEB nuclear translocation in H9C2 cardiomyocytes under GP treatment.Compared with control group,the TFEB nuclear translocation in H9C2 under GP was reduced.Compared with the GP+NC-siRNA group,the TFEB nuclear translocation was significantly enhanced in the GP+ADAM17-siRNA group.9.Cardiac autophagy was impaired in DCM mice and myocardial knockout of ADAM17 improved autophagy.Compared with the control group,the ratio of LC3?/? protein in the DM group was significantly decreased,and the p62 level was significantly increased,suggesting that autophagy was impaired.Myocardial knockout of ADAM 17 increased LC3II/I ratio and LAMP-2A protein level compared with ADAM17fl/fl DM mice.10.ADAM17 gene interference improved autophagy in H9C2 cells under GP.Using the GFP-RFP-LC3B autophagy detection tool,we found that GP impaired the autophagic flow of H9C2,and ADAM17-siRNA improved autophagy flow.Under GP,p62 protein expression was significantly increased and LAMP-2A was significantly decreased.ADAM17-si-RNA could reverse them.Conclusion1.Cardiomyocyte-specific ADAM17 knockout improved left ventricular systolic and diastolic fuction in DCM mice.2.Cardiomyocyte-specific ADAM17 knockout improved ventricular fibrosis and apoptosis.3.Cardiomyocyte-specific ADAM17 knockout up-regulated the protein level of ACE2 in cardiomyocytes.4.AMPK-TFEB-autophagy played a vital role in diabetic cardiomyopathy,which involved in the mechanisms of the cardioprotection of ADAM17 deficiency. |
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