Attenuation of beta2-adrenergic receptors and homocysteine metabolic enzymes cause diabetic cardiomyopathy.
Although adrenergic receptors (AR) and hyperhomocysteinemia (HHcy) are implicated in heart failure, their role in diabetic cardiomyopathy is not completely understood. We tested the hypothesis that glucose mediated depletion of beta2-AR and HHcy impair contractile function of cardiomyocytes leading to diabetic cardiomyopathy. To prove the hypothesis, cardiac function was assessed in 12week male diabetic Ins2+/- Akita and C57BL/6J mice by echocardiography, pressure-volume loop, and contractile function of cardiomyocytes. The results revealed cardiac dysfunction in Akita. To investigate the mechanism, the levels of beta2-AR, GLUT4, sarcoplasmic reticulum calcium ATP-ase-isoform 2 (SERCA-2) and homocysteine (Hcy) metabolic enzymes-cystathionine beta synthase (CBS), cystathionine gamma lyase (CTH), and methyl tetrahydrofolate reductase (MTHFR) were determined in the heart. It revealed down-regulation of beta2-AR, GLUT4, SERCA-2, CBS, CTH, and MTHFR in Akita. Attenuation of beta2-AR in hyperglycemic condition was also confirmed in cardiomyocytes at in vitro level. Interestingly, the ex vivo treatment of cardiomyocytes with beta2-AR antagonist deteriorated whereas beta-AR agonist ameliorated contractile function. It points to the involvement of beta2-AR in diabetic cardiomyopathy. We conclude that degradation of beta2-AR and impairment of Hcy metabolism is implicated in diabetic cardiomyopathy.
Mishra
Paras Kumar
PK
Department of Physiology & Biophysics, School of Medicine, University of Louisville, Louisville, KY 40202, USA. pkmish01@louisville.edu
Givvimani
Srikanth
S
Metreveli
Naira
N
Tyagi
Suresh C
SC
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D009202:Cardiomyopathies / Q000201:enzymology / Q000209:etiology*; D003541:Cystathionine beta-Synthase / Q000172:deficiency*; D003542:Cystathionine gamma-Lyase / Q000172:deficiency*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D005492:Folic Acid / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology; D006710:Homocysteine / Q000378:metabolism*; D006943:Hyperglycemia / Q000139:chemically induced / Q000235:genetics; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000209:etiology*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D051275:Glucose Transporter Type 4; D018343:Receptors, Adrenergic, beta-2; C495693:Slc2a4 protein, mouse; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; C506947:Atp2a2 protein, mouse; D005947:Glucose