AIM:To investigate the role and mechanisms of p21 activated kinase 1(Pak1)in myocardial met-abolic reprogramming(MR)in diabetes mellitus(DM)mice and its protective effects on cardiomyocytes.METHODS:Pak1flox/flox(Pak1f/f)mice and cardiomyocyte-specific Pak1 knockout(Pak1CKO)mice were randomly divided into 4 groups(n=6 per group):Pak1f/f group,Pak1f/f+DM group,Pak1CKO group,and Pak1CKO+DM group.Diabetes was induced by in-traperitoneal injection of streptozotocin.Cardiac function was evaluated by echocardiography 6 weeks after successful mod-eling.Ventricular myocardium was harvested after euthanasia.Myocardial pathological changes and lipid accumulation were assessed by HE staining and oil red O staining.Protein expression levels of Pak1,p-Pak1,peroxisome proliferator-activated receptor α(PPARα),PPARγ,lipoprotein lipase(LPL),carnitine palmitoyltransferase 1(CPT1),scavenger receptor B2(SCARB2/CD36),fatty acid binding protein 3(FABP3),pyruvate dehydrogenase kinase 4(PDK4)and the ratio of phosphorylated pyruvate dehydrogenase E1α subunit(p-PDHA1)to PDHA1 were determined by Western blot.The mRNA expression levels of diacylglycerol acyltransferase 1/2(DGAT1/2)were detected by RT-qPCR.RESULTS:Compared with Pak1f/f group,both Pak1f/f+DM and Pak1CKO groups showed significantly decreased left ventricular ejection fraction(EF)and fractional shortening(FS),as well as increased left ventricular end-diastolic volume(LV Vold)and end-systolic volume(LV Vols)(P<0.01).Significant myocardial pathological damage with excessive lipid accumulation was observed.Myocardial p-Pak1 and Pak1 protein expression decreased(P<0.01),while PPARα,PPARγ,CPT1,LPL,CD36,FABP3,and PDK4 protein expression significantly increased(P<0.01),along with elevated p-PDHA1/PDHA1 ratio(P<0.01).mRNA expression levels of DGAT1 and DGAT2 were significantly reduced(P<0.01).The Pak1CKO+DM group showed the same trend as the Pak1f/f+DM group but with greater severity;compared with the Pak1f/f+DM group,the Pak1CKO+DM group still showed significant differences in all indicators except EF,FS,and LVVold(P<0.05 or P<0.01).CONCLUSION:Myocardial Pak1 protein expression is suppressed in diabetic mice,which mediates MR through activation of the PPARα/γ signaling pathway,resulting in increased myocardial fatty acid uptake and utiliza-tion while reducing glucose oxidation capacity.This leads to lipid accumulation in cardiomyocytes,myocardial damage,and cardiac systolic and diastolic dysfunction.

AIM:To investigate the role and mechanisms of p21 activated kinase 1(Pak1)in myocardial met-abolic reprogramming(MR)in diabetes mellitus(DM)mice and its protective effects on cardiomyocytes.METHODS:Pak1flox/flox(Pak1f/f)mice and cardiomyocyte-specific Pak1 knockout(Pak1CKO)mice were randomly divided into 4 groups(n=6 per group):Pak1f/f group,Pak1f/f+DM group,Pak1CKO group,and Pak1CKO+DM group.Diabetes was induced by in-traperitoneal injection of streptozotocin.Cardiac function was evaluated by echocardiography 6 weeks after successful mod-eling.Ventricular myocardium was harvested after euthanasia.Myocardial pathological changes and lipid accumulation were assessed by HE staining and oil red O staining.Protein expression levels of Pak1,p-Pak1,peroxisome proliferator-activated receptor α(PPARα),PPARγ,lipoprotein lipase(LPL),carnitine palmitoyltransferase 1(CPT1),scavenger receptor B2(SCARB2/CD36),fatty acid binding protein 3(FABP3),pyruvate dehydrogenase kinase 4(PDK4)and the ratio of phosphorylated pyruvate dehydrogenase E1α subunit(p-PDHA1)to PDHA1 were determined by Western blot.The mRNA expression levels of diacylglycerol acyltransferase 1/2(DGAT1/2)were detected by RT-qPCR.RESULTS:Compared with Pak1f/f group,both Pak1f/f+DM and Pak1CKO groups showed significantly decreased left ventricular ejection fraction(EF)and fractional shortening(FS),as well as increased left ventricular end-diastolic volume(LV Vold)and end-systolic volume(LV Vols)(P<0.01).Significant myocardial pathological damage with excessive lipid accumulation was observed.Myocardial p-Pak1 and Pak1 protein expression decreased(P<0.01),while PPARα,PPARγ,CPT1,LPL,CD36,FABP3,and PDK4 protein expression significantly increased(P<0.01),along with elevated p-PDHA1/PDHA1 ratio(P<0.01).mRNA expression levels of DGAT1 and DGAT2 were significantly reduced(P<0.01).The Pak1CKO+DM group showed the same trend as the Pak1f/f+DM group but with greater severity;compared with the Pak1f/f+DM group,the Pak1CKO+DM group still showed significant differences in all indicators except EF,FS,and LVVold(P<0.05 or P<0.01).CONCLUSION:Myocardial Pak1 protein expression is suppressed in diabetic mice,which mediates MR through activation of the PPARα/γ signaling pathway,resulting in increased myocardial fatty acid uptake and utiliza-tion while reducing glucose oxidation capacity.This leads to lipid accumulation in cardiomyocytes,myocardial damage,and cardiac systolic and diastolic dysfunction.