Research Report 2010 - MDC

Maik GollaschStructure of the GroupGroup LeaderProf. Maik GollaschGraduate students andclinical fellowsJohanna SchleifenbaumCarolin KöhnMirija WechslerMarwan MannaaDr. Alexander WutzlerAssociated scientistsDr. Kirill EssinDr. Galyna DubrovskaTechnical AssistantsYoland-Marie AnistanDiana HeroldManager of sponsoredprogramsSusanne WisslerSmooth Muscle Cell Electrophysiology,Ion Channel, and Transporter FunctionIon channels and electrophysiologyThis group focuses on ion channels, primarily in vascularsmooth muscle cells (VSMC), to clarify mechanismscontributing to hypertension and cardiovascular disease.Calcium-activated potassium (BK) channels havereceived special attention. The group collaborated withRalph Kettritz to study the notion that BK channels areinvolved in neutrophil activation. A knockout mousemodel showed convincingly that BK channels are notinvolved in this process. The group investigated the roleof transient receptor potential (TRP) ion channels inagonist-independent G(q 11) protein-coupled receptoractivation. Their work showed that G(q 11)-coupledreceptors could function as membrane stretch receptorsin VSMC. A close collaboration with Wolf-HagenSchunck at the MDC has turned the group’s focustowards eicosanoids. The group found that p450eicosanoids such as epoxyeicosatrienoic acids arevasodilatory, largely through their ability to activateendothelial NO synthase and NO release. Furthermore,in collaboration with Huang Yu in Hong Kong, theyfound that endothelium-derived contracting factors aredependent on cyclooxygenase-2. Another area ofresearch is directed towards identifying the role of theperivascular fat as a modulator of arterial tone, withspecific emphasis on the resistance vasculature.BK channels and neutrophil functionThe group (in collaboration with Ralph Kettritz (ECRC)and William Nauseef (University of Iowa) was involvedin an “intensive” controversy with a group at UniversityCollege London, regarding the importance of BK channelsin the mediation of neutrophil “burst” reactions. Totest this notion, Kirill Essin and the group directlyassessed the role of BK channels in neutrophil function,including the NADPH oxidase. Neutrophils lacking BKchannels (BK-/-) had normal intracellular and extracellularNADPH oxidase activity in response to both receptor-independentand phagocytic challenges. Furthermore,NADPH oxidase activity of neutrophils andmacrophages was normal after treatment with BKchannel inhibitors. Although BK channel inhibitors suppressedendotoxin-mediated tumor necrosis factoralphasecretion by bone marrow-derived macrophages,cells from BK-/- and wild-type mice responded identicallyand exhibited the same ERK, PI3K/Akt, and NF-κBactivation. The group concluded that the BK channel isnot required for NADPH oxidase activity in neutrophils.The contentious argument has been dropped.Epoxyeicosatrienoic acids (EETs)EETs serve as endothelial-derived hyperpolarizing factors(EDHF), but may also affect vascular function byother mechanisms. The Gollasch team identified anovel interaction between EETs and endothelial NOrelease using soluble epoxide hydrolase (sEH) -/- and+/+ mice. EDHF responses to acetylcholine in pressurizedisolated mesenteric arteries were neither affectedby the sEH inhibitor, N-adamantyl-N’-dodecylurea(ADU), nor by sEH gene deletion. However, the EDHFresponses were abolished by catalase and byapamin/charybdotoxin (ChTx), but not by iberiotoxin,nor by the cytochrome P450 inhibitor PPOH. All fourEETs (order of potency: 8,9-EET >14,15-EET approximately5,6-EET >11,12-EET) and all 4 dihydroxy derivatives(14,15-DHET approximately 8,9-DHET approximately11,12-DHET >5,6-DHET) produced dose-dependentvasodilation. Endothelial removal or L-NAME blocked8,9-EET and 14,15-DHET-dependent dilations. Theeffects of apamin/ChTx were minimal. 8,9-EET and14,15-DHET induced NO production in endothelial cells.ADU (100 µg/ml in drinking water) lowered blood pres-214 The Experimental and Clinical Research Center