Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes

Abstract

Changes in the lipid composition of cardiac myocytes have been reported during cardiac hypertrophy, cardiomyopathy, and infarction. Because a recent study indicates a relation between low phosphatidylinositol-bisphosphate (PIP 2 ) levels and reduced intercellular coupling, we tested the hypothesis that agonist-induced changes in PIP 2 can result in a reduction of the functional coupling of cardiomyocytes and, consequently, in changes in conduction velocity. Intercellular calmodulin, or arachidonic acid production did not affect the response to either angiotensin II or noradrenaline. Furthermore, decreasing or increasing PIP 2 also decreased and increased intercellular coupling, respectively. This supports the role of PIP 2 in the regulation of intercellular coupling. In beating myocytes, conduction velocity was reduced by angiotensin II stimulation, and recovery after wash out was prevented by inhibition of PIP 2 production. Reductions in PIP 2 inhibit intercellular coupling in cardiomyocytes, and stimulation by physiologically relevant agonists reduces intercellular coupling by this mechanism. The reduction in intercellular coupling lowered conduction velocity.

Norepinephrine inhibits intercellular coupling in rat cardiomyocytes by ubiquitination of connexin43 gap junctions

“…In accordance with our previous studies (Hofgaard et al 2008), exposure of neonatal rat ventricular cardiomyocytes to norepinephrine (1 μ M) for 10 min reduced dye transfer of Lucifer yellow to 68 % compared to untreated controls (Figure 2). Uncoupling was partially prevented in cells pre-incubated with the proteasomal inhibitor MG132 (20 μ M) or the lysosomal inhibitor leupeptin (100 μ M) before exposure to norepinephrine.…”

“…Previous studies from our lab show that the G α q agonists, norepinephrine and angiotensin II, reduce intercellular coupling in neonatal rat ventricular cardiomyocytes (Hofgaard et al, 2008). In primary cultures of pulmonary artery endothelial cells, G α q stimulation leads to internalization of Cx43 (Baker et al, 2008).…”

“…Intercellular diffusion of Lucifer yellow was measured with the EPIZAP system (Ask Science Products, Kingston, ON, Canada) as previously described (Hofgaard et al, 2008;Hofgaard et al, 2009). Briefly, cells growing on glass slides partly covered by an electrically conductive layer were electroporated to allow Lucifer yellow to enter the cells.…”

“…We have previously reported that stimulation of G α q -coupled receptors by either norepinephrine or angiotensin II reduces intercellular coupling in primary cultures of neonatal rat ventricular cardiomyocytes (Hofgaard et al, 2008). The response to G α q stimulation is maximal after 10 min of agonist exposure, and intercellular coupling recovers to control levels after 10 min incubation in agonist free medium.…”

Panhistone deacetylase inhibitors inhibit proinflammatory signaling pathways to ameliorate interleukin-18-induced cardiac hypertrophy

“…The phosphainositide lipid second messengers are involved in intracellular coupling of cardiac myocytes (25). In addition to the involvement of PI3K, a number of prominent kinase (CaM kinase, mTOR, and MAPK)-and phosphatase (calcineurin, MKP)-specific networks were seen in our study; these are known to integrate cellular responses to many stimuli, including IFN␥ and TNF-␣ and chemokines (3,4,6,32,38,57,61).…”