Modulation of atrial contraction by PKA and PKC during the compensated phase of eccentric cardiac hypertrophy

Abstract

Calcium homeostasis is intimately regulated by protein kinase phosphorylation cascades that are also involved in the induction and maintenance of cardiac hypertrophy. In addition, the development of cardiac hypertrophy has been associated with alteration in the activation of the adrenergic system. Therefore, we investigated the specific role of protein kinase A (PKA) and C (PKC) on cardiac muscle contractile activity in the presence and absence of adrenergic stimulation. Isolated left atrial preparations from sham- and volume overload-induced cardiac hypertrophied rats were superfused with Tyrode and electrically stimulated at 0.75 Hz. Contraction was assessed in the basal and pre-stimulated (norepinephrine, 10(-9)M) states. Specific inhibitors, KT 5720 for PKA and Ro-32-0432 for PKC, were used. Peak tension development in left atria from sham-operated rats was more sensitive to PKC- than PKA-inhibition, whereas this differential sensitivity was abolished in the hypertrophied hearts. This difference was mainly due to an increase in the role of PKA in the contractile response. Developed peak tension by left atria from shunt rats was higher than that from sham rats, but when expressed to relative tissue mass, hypertrophied muscle showed weaker contraction than that from the sham group. In addition, the left atrial velocity of contraction in the sham is PKA-sensitive, while that of the shunt is PKC-sensitive. Furthermore, the velocity of relaxation shows dependency on both protein kinases, with PKC having a greater effect than PKA in the hypertrophied group. NE increased the PTD and the velocity of contraction (+dT/dt) through PKA and PKC dependent mechanisms, without affecting the velocity of relaxation (-dT/dt) in atrial muscle from sham rats. In contrast, during eccentric hypertrophy NE effectively reduced PTD as well as the -dT/dt through a PKC-dependent mechanism. The present study demonstrates that during early development of moderate eccentric cardiac hypertrophy there is: (1) a reduced specific peak tension developed due to an imbalance in the PKA and PKC activation; (2) a change in the protein kinase dependence of the velocity of contraction and relaxation from PKA to PKC with atrial hypertrophy; and (3) a negative inotropic response to adrenergic receptor stimulation. These functional responses may play a critical role in the cardiac performance during the progression of eccentric cardiac hypertrophy into the decompensated phase and heart failure.

Restoration of diabetes-induced abnormal local Ca2+release in cardiomyocytes by angiotensin II receptor blockade

“…We previously reported that, in a rat model of STZ-induced diabetes, a prominent abnormal Ca 2ϩ leak occurs through the RyR2, owing to a partial loss of RyR2-bound FKBP12.6 and PKA-mediated hyperphosphorylation of RyR2 (51). Both protein kinases, PKA and PKC, are expressed in cardiac muscle (22), and they strongly controlled cardiac inotropic activity (17,19,45). PKA and PKC play a central role in transducing signal and potentiating intracellular cross talk by phosphorylating diverse substrates, including receptors, enzymes, and transcription factors.…”

Phosphodiesterase inhibitor KMUP‐3 displays cardioprotection via protein kinase G and increases cardiac output via G‐protein‐coupled receptor agonist activity and Ca2+ sensitization

“…PKA increases open the L‐type calcium channel, leading to calcium influx and Ca 2+ release from the sarcoplasmic reticulum in cardiomyocytes via an excitation–contraction coupling pathway. Continuous stimulation of cAMP/PKA has calcium overloading potential and the resultant cardiac arrhythmia and myocardial cell injury has been considered the primary defect of PDE‐3 inhibitors [33,34]. The electrically stimulated right atrial contractility shown by KMUP‐3 is inhibited by the sGC inhibitor ODQ, indicating the involvement of cGMP.…”

Prenatal cocaine alone and combined with nicotine alters ANG II and IGF-1 induced left atrial contractions in aging male offspring

“…We have recently shown that in rats the atrial velocities of contraction and relaxation are also mainly dependent on PKA activation (Haddad et al 2004). In addition, nicotine has been shown to activate ERK and PKA (Dajas-Bailador et al 2002;Hsu et al 1997).…”