Dokument

Zusammenfassung:
Die Bedeutung des vaskulären Endothels für die Regulation der kardiovaskulären Homeostase ist, aufgrund einer zunehmenden Zahl an Daten, offensichtlich geworden. Die endotheliale Aktivierung und Dysfunktion spielt eine bedeutende Rolle bei der Pathogenese zahlreicher kardiovaskulärer Erkrankungen. Um ihre Aufgaben erfüllen zu können, exprimieren Endothelzellen eine Vielzahl von membranständigen Ionenkanälen. Besondere Bedeutung weist dabei die Kontrolle des Ca2+-Einstroms und die Modulation des Membranpotentials der Endothelzelle auf. Die Veränderung der [Ca2+]i erfolgt sowohl über die Freisetzung von Ca2+ aus dem Intrazellulärraum als auch durch den Ca2+-Einstrom von außerhalb der Zelle. Der extrazelluläre Ca2+-Einstrom wird unter anderem über nicht-selektive Kationenkanäle vermittelt. Zu diesen gehören die 28 humanen Mitglieder der TRP-Familie. Die Bedeutung der TRP-Kanäle in humanen Endothelzellen ist bislang nicht abschließend geklärt. Das Ziel dieser Arbeit war die systematische Untersuchung der Expression aller humanen TRP-Kanäle in humanen dermalen mikrovaskulären Endothelzellen (HMEC-1) mittels der etablierten Methode der Real-Time RT-PCR. Als house-keeping-Gen diente GAPDH, als endothelialer Marker vWF, deren Expression ebenfalls untersucht wurden. Zur Verifizierung der durch RT-PCR gewonnenen Daten erfolgte von jeder durchgeführten RT-PCR eine Gelelektrophorese. Zusätzlich wurde die Qualität jedes Primers mittels Linearitätsanalysen validiert. Hierbei konnte die Expression der mRNA von TRPC1, TRPC3, TRPC4, TRPC6 und TRPC7, TRPV1, TRPV2 sowie TRPV4, TRPM4, TRPM5, TRPM6, TRPM7 und TRPM8, TRPA1, TRPML2, TRPP1 und PKD2like1 gezeigt werden. Von diesen TRP-Kanälen war eine besonders hohe Expression von TRPC1, TRPC4, TRPC6, TRPM6, TRPM7, TRPM8 sowie TRPP1 nachweisbar. Da wenig bekannt ist über die Aktivierung und Modulation von TRP-Kanälen in Endothelzellen, wurde anschließend mittels RT-PCR untersucht, ob die Stimulation der HMEC-1 mit verschiedenen vasoaktiven (Bradykinin, Histamin, Endothelin-1) und pro-angiogenetischen Faktoren (VEGF, Erythropoetin) zu einer Modulation der Expression der 28 humanen TRP-Kanäle in HMEC-1 führt. Auch hier wurden mittels Gelelektrophorese die gewonnenen Daten der RT-PCR bestätigt. Hierbei konnte nach Stimulation mit VEGF eine signifikant erhöhte Expression von TRPM8 aufgezeigt werden, ebenso war nach Stimulation mit Bradykinin eine signifikant erhöhte Expression von TRPM4, TRPM5 und TRPM8 aufzuweisen. Insgesamt konnte anhand der Ergebnisse der vorliegenden Studie bestätigt werden, dass humane mikrovaskuläre Endothelzellen von Typ HMEC-1 spezifische TRP-Kanäle exprimieren. Des Weiteren konnte gezeigt werden, dass die Expression einiger dieser Kanäle nach endothelialer Stimulation erhöht wird. Somit konnte anhand der Stimulationsversuche gezeigt werden, dass vasoaktive und pro-angiogenetische Faktoren die Expression der TRP-Kanäle im Endothel modulieren können. Entgegen der Erwartungen war keine jedoch keine deutlich intensivere Expression einzelner TRP-Kanäle, trotz statischer Signifikanz nach Stimulation der HMEC-1, zu beobachten. Das bessere Verständnis der physiologischen Funktion des Endothels und des vaskulären Systems liefert den Schlüssel zum Verständnis pathophysiologischer Prozesse und eröffnet neue therapeutische Perspektiven. So ist es vorstellbar, dass in Zukunft TRP-Kanäle aufgrund ihrer komplexen Funktionen im kardiovaskulären System an Bedeutung für die Entwicklung neuer Pharmaka gewinnen.

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