Details

Autor(en) / Beteiligte

• Liang, Wenbin
• Oudit, Gavin Y
• Patel, Mikin M
• Shah, Ajay M
• Woodgett, James R
• Tsushima, Robert G
• Ward, Michael E
• Backx, Peter H

Titel

Role of Phosphoinositide 3-Kinase α, Protein Kinase C, and L-Type Ca2+ Channels in Mediating the Complex Actions of Angiotensin II on Mouse Cardiac Contractility

Ist Teil von

• Hypertension (Dallas, Tex. 1979), 2010-09, Vol.56 (3), p.422-429

Ort / Verlag

Hagerstown, MD: American Heart Association, Inc

Erscheinungsjahr

2010

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Although angiotensin II (Ang II) plays an important role in heart disease associated with pump dysfunction, its direct effects on cardiac pump function remain controversial. We found that after Ang II infusion, the developed pressure and +dP/dtmax in isolated Langendorff-perfused mouse hearts showed a complex temporal response, with a rapid transient decrease followed by an increase above baseline. Similar time-dependent changes in cell shortening and L-type Ca currents were observed in isolated ventricular myocytes. Previous studies have established that Ang II signaling involves phosphoinositide 3-kinases (PI3K). Dominant-negative inhibition of PI3Kα in the myocardium selectively eliminated the rapid negative inotropic action of Ang II (inhibited by ≈90%), whereas the loss of PI3Kγ had no effect on the response to Ang II. Consistent with a link between PI3Kα and protein kinase C (PKC), PKC inhibition (with GF 109203X) reduced the negative inotropic effects of Ang II by ≈50%. Although PI3Kα and PKC activities are associated with glycogen synthase kinase-3β and NADPH oxidase, genetic ablation of either glycogen synthase kinase-3β or p47 (an essential subunit of NOX2-NADPH oxidase) had no effect on the inotropic actions of Ang II. Our results establish that Ang II has complex temporal effects on contractility and L-type Ca channels in normal mouse myocardium, with the negative inotropic effects requiring PI3Kα and PKC activities.