Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Crnkovic, S.
MECHANISMS BEHIND OMEGA-3 FATTY ACIDS` ANTI-PROLIFERATIVE EFFECT ON HUMAN PULMONARY ARTERY SMOOTH MUSCLE CELLS
[ Dissertation ] Medical University of Graz; 2013. pp. 104
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- Autor*innen der Med Uni Graz:
- Crnkovic Slaven
- Betreuer*innen:
- Frank Sasa
- Olschewski Andrea
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- Abstract:
- Proliferation of vascular smooth muscle cells is a characteristic of pathological vascular remodeling and represents a significant therapeutic challenge in several cardiovascular diseases. Docosahexaenoic acid (DHA), a member of n-3 polyunsaturated fatty acids (n-3 PUFA), was shown to inhibit proliferation of numerous cell types implicating several different mechanisms. In the present study we examined molecular events underlying the inhibitory effect of DHA on proliferation of primary human smooth muscle cells isolated from small pulmonary arteries (hPASMC). DHA concentration-dependently inhibited hPASMC proliferation, induced G1 cell cycle arrest and decreased cyclin D1 protein expression. DHA activated the unfolded protein response (UPR), evidenced by increased mRNA expression of HSPA5, increased phosphorylation of eukaryotic initiation factor 2 alpha (eIF-2¿) and splicing of X-box binding protein 1 (XBP-1). DHA altered the cellular lipid composition and led to increased reactive oxygen species (ROS) production. DHA-induced ROS was dependent on both, intracellular Ca2+ release and entry of extracellular Ca2+. Overall, cellular ROS and mitochondrial ROS were decreased by RU360, a specific inhibitor of mitochondrial Ca2+ uptake. DHA ¿induced mitochondrial dysfunction was evidenced by decreased mitochondrial membrane potential (¿¿m) and decreased cellular ATP content. DHA triggered apoptosis as found by increased number of cleaved caspase-3 and TUNEL positive cells. Free radical scavenger, Tempol, counteracted DHA-induced ROS, cell cycle arrest, induction of UPR and apoptosis. We concluded that Ca2+-dependent oxidative stress is the central and initial event responsible for the induction of UPR, cell cycle arrest and apoptosis in DHA-treated hPASMC.