Abstract
β-adrenergic system is the major system regulating cardiac function under “fight-or-flight” situations. Recently it has been reported that PKA-independent mechanisms such as exchange protein directly activated by cAMP (EPAC) and PKA-independent activation of Ca/calmodulin dependent kinase II (CaMK II) also play a role in the “fight-or-flight” response (FFR). To study the relative contribution of PKA, CaMK II and EPAC to the FFR, transgenic mice (4m) with specific inhibition of PKA (PKI) and myocytes were used to determine cardiac or myocyte responses to β-adrenergic stimulation. Results: 1 . PKI was fully expressed at the age of 4 months and did not interfere with the production of cAMP induced by β-AR stimulation and the activation of CaMK II by high extracellular Ca, indicating no alteration of the components of β-AR/Gs/AC signaling pathway; 2 . ECHO showed that at baseline, the fractional shortening (FS: PKI: 38.7±1.5%; ctr: 39.0±2.1%) and ejection fraction (EF: PKI: 66.8±3.2%; ctr: 68.9.0±4.1%) were not significantly different between groups; ISO increased heart rate (HR: ctr: from 412±11bpm to 613±23bpm; PKI: from 425±13bpm to 430±21bpm), EF (ctr: 85.6±3.3%; PKI: 70.8±2.9%) and FS (ctr: 57.0±4.5%; PKI: 39.5±2.7%) in ctr but not in PKI mice. 3 . At baseline, maximal dp/dt (ctr: 6980±197mmHg/s; PKI: 7204±200mmHg/s) and minimum -dp/dt (ctr: -6248±214mmHg/s; PKI: 6587±304mmHg/s) were not different; ISO increased the HR, dp/dt (ctr: 1298±246mmHg/s; PKI: 7264±156mmHg/s) and -dp/dt (ctr: 7588±390mmHg; PKI: -5607±414mmHg) in ctr but not in TG mice. 4 . ISO increased Ca current, contraction, Ca transient and SR Ca content in ctr myocytes but not in TG myocytes. 5 . The phosphorylation of phospholamban at the PKA site (ser16) and CaMK II site (thr17) induced by ISO was blocked by PKI but not in ctr hearts, indicating that CaMK II is downstream to PKA. 6 . An EPAC activator, 8-cp-TOME-AM, could not increase cardiac performance of Langendorff perfused PKI hearts although it did slightly enhance cardiac function of ctr hearts, maybe due to its inhibitory effects on phosphodiesterases. Conclusion: PKA and its downstream CaMK II are the mediators of the “fight-or-flight” responses. Other PKA-independent pathways may not play a significant role.
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