UMR-S 1180, INSERM, Univ. Paris-Sud, Université Paris-Saclay, Orsay, France.
ACTAGen, UMS IPSIT, Univ. Paris-Sud, Université Paris Saclay, Orsay, France.
PLoS One. 2023 Sep 21;18(9):e0292015. doi: 10.1371/journal.pone.0292015. eCollection 2023.
The beta-adrenergic system is a potent stimulus for enhancing cardiac output that may become deleterious when energy metabolism is compromised as in heart failure. We thus examined whether the AMP-activated protein kinase (AMPK) that is activated in response to energy depletion may control the beta-adrenergic pathway. We studied the cardiac response to beta-adrenergic stimulation of AMPKα2-/- mice or to pharmacological AMPK activation on contractile function, calcium current, cAMP content and expression of adenylyl cyclase 5 (AC5), a rate limiting step of the beta-adrenergic pathway. In AMPKα2-/- mice the expression of AC5 (+50%), the dose response curve of left ventricular developed pressure to isoprenaline (p<0.001) or the response to forskolin, an activator of AC (+25%), were significantly increased compared to WT heart. Similarly, the response of L-type calcium current to 3-isobutyl-l-methylxanthine (IBMX), a phosphodiesterase inhibitor was significantly higher in KO (+98%, p<0.01) than WT (+57%) isolated cardiomyocytes. Conversely, pharmacological activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) induced a 45% decrease in AC5 expression (p<0.001) and a 40% decrease of cAMP content (P<0.001) as measured by fluorescence resonance energy transfer (FRET) compared to unstimulated rat cardiomyocytes. Finally, in experimental pressure overload-induced cardiac dysfunction, AMPK activation was associated with a decreased expression of AC5 that was blunted in AMPKα2-/- mice. The results show that AMPK activation down-regulates AC5 expression and blunts the beta-adrenergic cascade. This crosstalk between AMPK and beta-adrenergic pathways may participate in a compensatory energy sparing mechanism in dysfunctional myocardium.
β肾上腺素能系统是增强心输出量的有力刺激因素，但在能量代谢受损（如心力衰竭时）时可能会产生有害作用。因此，我们研究了 AMP 激活的蛋白激酶（AMPK）是否可以控制β肾上腺素能途径，该激酶在能量耗竭时被激活。我们研究了 AMPKα2-/- 小鼠的心脏对β肾上腺素能刺激的反应，以及药物激活 AMPK 对收缩功能、钙电流、cAMP 含量和腺苷酸环化酶 5（AC5）表达的影响，AC5 是β肾上腺素能途径的限速步骤。与 WT 心脏相比，在 AMPKα2-/- 小鼠中，AC5 的表达增加了 50%（p<0.001），左心室发展压力对异丙肾上腺素的剂量反应曲线（p<0.001）或对 forskolin（AC 的激活剂）的反应增加了 25%。同样，分离的 KO 心肌细胞中 L 型钙电流对 3-异丁基-1-甲基黄嘌呤（IBMX）的反应（一种磷酸二酯酶抑制剂）也显著高于 WT 心肌细胞（增加 98%，p<0.01）。相反，用 5-氨基咪唑-4-甲酰胺核苷（AICAR）药物激活 AMPK，与未刺激的大鼠心肌细胞相比，AC5 表达减少了 45%（p<0.001），cAMP 含量减少了 40%（p<0.001），这是通过荧光共振能量转移（FRET）测量的。最后，在实验性压力超负荷诱导的心脏功能障碍中，AMPK 激活与 AC5 表达减少有关，而在 AMPKα2-/- 小鼠中，这种减少作用减弱。结果表明，AMPK 激活下调 AC5 表达并使β肾上腺素能级联反应减弱。AMPK 和β肾上腺素能途径之间的这种串扰可能参与了功能障碍心肌中的一种节能补偿机制。
