Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.4.1.2 (acetyl-CoA carboxylase)
 2,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II induces cardiomyocyte hypertrophy, but its consequences on cardiomyocyte metabolism and energy supply are not completely understood. Here we investigate the effect of angiotensin II on glucose and fatty acid utilization and the modifying role of AMP-activated protein kinase (AMPK), a key regulator of metabolism and proliferation. Treatment of H9C2 cardiomyocytes with angiotensin II (Ang II, 1 microm, 4 h) increased [(3)H]leucine incorporation, up-regulated the mRNA expression of the hypertrophy marker genes MLC, ANF, BNP, and beta-MHC, and decreased the phosphorylation of the negative mTOR-regulator tuberin (TSC-2). Rat neonatal cardiomyocytes showed similar results. Western blot analysis revealed a time- and concentration-dependent down-regulation of AMPK-phosphorylation in the presence of angiotensin II, whereas the protein expression of the catalytic alpha-subunit remained unchanged. This was paralleled by membrane translocation of glucose-transporter type 4 (GLUT4), increased uptake of [(3)H]glucose and transient down-regulation of phosphorylation of acetyl-CoA carboxylase (ACC), whereas fatty acid uptake remained unchanged. Similarly, short-term transaortic constriction in mice resulted in down-regulation of P-AMPK and P-ACC but up-regulation of GLUT4 membrane translocation in the heart. Preincubation of cardiomyocytes with the AMPK stimulator 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR; 1 mM, 4 h) completely prevented the angiotensin II-induced cardiomyocytes hypertrophy. In addition, AICAR reversed the metabolic effects of angiotensin II: GLUT4 translocation was reduced, but ACC phosphorylation and TSC phosphorylation were elevated. In summary, angiotensin II-induced hypertrophy of cardiomyocytes is accompanied by decreased activation of AMPK, increased glucose uptake, and decreased mTOR inhibition. Stimulation with the AMPK activator AICAR reverses these metabolic changes, increases fatty acid utilization, and inhibits cardiomyocyte hypertrophy.
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PMID:Metabolic switch and hypertrophy of cardiomyocytes following treatment with angiotensin II are prevented by AMP-activated protein kinase. 1879 Jul 41

Losartan is a selective angiotensin II (Ang II) type 1 (AT(1)) receptor antagonist which inhibits vascular smooth muscle cells (VSMCs) contraction and proliferation. We hypothesized that losartan may prevent cell proliferation by activating AMP-activated protein kinase (AMPK) in VSMCs. VSMCs were treated with various concentrations of losartan. AMPK activation was measured by Western blot analysis and cell proliferation was measured by MTT assay and flowcytometry. Losartan dose- and time-dependently increased the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in VSMCs. Losartan also significantly decreased the Ang II- or 15% FBS-induced VSMC proliferation by inhibiting the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. Compound C, a specific inhibitor of AMPK, or AMPK siRNA blocked the losartan-induced inhibition of cell proliferation and the G(0)/G(1) cell cycle arrest. These data suggest that losartan-induced AMPK activation might attenuate Ang II-induced VSMC proliferation through the inhibition of cell cycle progression.
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PMID:Losartan Inhibits Vascular Smooth Muscle Cell Proliferation through Activation of AMP-Activated Protein Kinase. 2116 28

Recent studies have shown that angiotensin-converting enzyme 2 (ACE2)/angiotensin (Ang) -(1-7)/Mas axis activation is able to improve the metabolic profile, enhance glucose tolerance and insulin sensitivity, improve metabolic parameters, and counteract deleterious effects of Ang II. The effects of endogenous ACE 2 activation on the metabolic profile of mice are poorly studied. In this study, 12 weeks old male mice were treated with the ACE 2 activator (diminazene aceturate, DIZE, 1 mg/kg/day, gavage) or saline (control) for 30 days followed by glucose tolerance tests, insulin sensitivity tests, and blood analysis. Epididymal ACE2, ACE, angiotensinogen, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) were measured by quantitative RT-PCR. ACE 2 activation treatment lowered body weight (DIZE vs control) (28.69 vs 30.28g, P < 0.001), serum cholesterol (140,0 vs 177.5; P < .05), and serum triglycerides (75,00 vs 165,0; P < .05) as well as epididymal (0.008 vs 0.016; P < .05) and retroperitoneal (0.0024 vs. 0.0068; P < .01) adipose tissue weights. These effects were associated with significantly increased epididymal ACE 2 and decreased ACE and angiotensinogen (AGT) expression. Additionally, DIZE decreased adipogenesis-related gene transcription, such as ACC and FAS mRNA. In conclusion, these results indicate that activation of ACE2 by oral DIZE treatment improves the metabolic profile and reduces fat deposition in mice. These results, along with the reduction of lipogenesis markers open a new perspective for metabolic disorder pharmacotherapy.
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PMID:Angiotensin converting enzyme 2 activator (DIZE) modulates metabolic profiles in mice, decreasing lipogenesis. 2566 42