Zusammenfassung
Bei älteren Patienten kommt es häufig als Folge eines nicht ausreichend behandelten
Bluthochdrucks zu einer Hypertrophie der Kardiozyten, die mehrere Defekte in der Genexpression
aufweisen. Es spricht vieles dafür, dass die verminderte Expression des Transkriptionsfaktors
PPARα eine reduzierte Fettsäurenoxidation auslöst, die - sofern kompensatorisch die
Glukoseoxidation gesteigert werden kann - als günstig eingestuft wird. Es verbleiben
aber verminderte PPARα-Einflüsse auf z. B. anti-inflammatorische Mechanismen. Es stellt
sich daher die Frage, ob es Pharmaka gibt, die zu einer Normalisierung reduzierter
PPARα-Wirkungen führen, ohne dass die Fettsäurenoxidation gesteigert wird. Als Leitsubstanz
dieser „Fettsäurenoxidationshemmer mit PPARα-Aktivierung” wurde Etomoxir, ein Hemmer
der Carnitin-Palmitoyl-Transferase-1 charakterisiert, das zu einer Steigerung der
Ca2+ -Pumpe des sarkoplasmatischen Retikulums, einer schnelleren Relaxation und einer verlangsamten
Progression der Herzinsuffizienz im Tierversuch führt. Es sollte daher geprüft werden,
ob die eingeschränkte Funktion druckbelasteter hypertrophierter Kardiozyten vor allem
älterer Patienten ein Therapieziel sein sollte, bevor es zur Progression der Herzinsuffizienz
und Symptomen wie Kurzatmigkeit kommt.
Summary
In elderly patients, an inadequately treated high blood pressure often leads to hypertrophied
cardiomyocytes with various defects in gene expression. Due to a decreased expression
of the transcription factor PPARα, fatty acid oxidation is reduced. If it can be compensated
by an increased glucose oxidation, it has been considered as a favorable process.
Nonetheless, reduced PPARα influences ensue involving e. g. anti-inflammatory mechanisms.
The question arises thus whether drugs can normalize reduced PPARα effects without
increasing fatty acid oxidation. As lead compound of these „fatty acid oxidation inhibitors
with PPARα activation”, the carnitine palmitoyltransferase-1 inhibitor etomoxir was
characterized. An increased expression and activity of the Ca2+ pump of sarcoplasmic reticulum, a faster relaxation and a slowed progression of heart
failure was observed in animal experiments. It should, therefore, be examined whether
the impaired function of pressure overloaded hypertrophied cardiomyocytes of particularly
elderly patients should be a therapeutic target before progression of heart failure,
neuroendocrine activation and symptoms such as shortness of breath occur.
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Prof. Dr. Heinz Rupp
Molekular-kardiologisches Labor
Karl-von-Frisch-Straße 1
35033 Marburg
Telefon: 06421/2865032
Fax: 06421/2868964
eMail: Rupp@staff.uni-marburg.de