Simvastatin friend or foe in abdominal aortic aneurysm

Transcription

1 Simvastatin friend or foe in abdominal aortic aneurysm A. Piechota-Polańczyk Department of Medical Biotechnology, Jagiellonian University, Krakow, Poland VISAR, Vienna, April 20-21, 2017

2 Statins in Abdominal aortic aneurysm treatment According to the European Society for Vascular Surgery guidelines for the management of AAA, statins and anti-platelet drugs should be used in patients diagnosed with AAA. Moll et al. Eur J Vasc Endovasc Surg (2011) Large meta-analysis showed that statins reduce the rate of progression of AAA. Takagi et al. Eur J Vasc Endovasc Surg (2012) One week of statins administered to patients undergoing OSR or EVAR was associated with improved survival during 1 year after surgery and a decreased incidence of lower extremity embolic complications after EVAR. Galinanes et al. Vascular (2014)

3 Oxidative and inflammatory balance in AAA under statin NF-kB signaling pathway Simvastatin decreases free radical formation and p=0.018 activation of NF-kB in AAA wall pp65 p65 β-tubulin

4 CyPA/GAPDH EMMPRIN/GAPDH Simvastatin ROS CyPA relation in human AAA Simvastatin decreases cyclophilin A expression and activation of ERK1/2 in AAA wall

5 The influence of statins on HO-1 and HO-1- related signaling pathways in vascular cells oxldl HMG-CoA Mevolanate Isopentenyl-PP STATINS Fernesyl-PP Pretenylation of proteins e.g. Rho, Ras, Rap, lamins p38 MAPK PI3K/Akt NF-kB Nrf2 oxidative stress, inflammation, matrix degradation, coagulation ROS, RNS HO-1 cell survival heme anti-oxidative and anti-inflammatory parameters Fe 2+ Biliverdin CO Piechota-Polanczyk and Jozkowicz, Curr Drug Targets 2016 Piechota-Polanczyk et al. Front Cardiovasc Med. 2015

6 Elevated protein level of HMOX-1 in simvastatin treated patients with AAA Simvastatin increases HMOX-1 expression and glutathione level in AAA wall P value- T-test

7 Decreased level of HO-1 ameliorates vascular injury HMOX-1 gene promoter demage demage Lipid accumulation Atherosclerotic lesions in HO-1 -/- and ApoE -/- mice 8 weeks after high fat diet implantation. In humans the level of HO-1 expression is modulated by the polymorphism of the microsatellite of the HMOX-1 gene promoter. Longer promoter with more guanidine thymidine (GT) repeats (n 29) = lower basal expression of HMOX-1 and lesser upregulation after stimulation. Patients with AAA have significantly higher level of long (GT) n repeat (n>32). HO-1 +/- with ApoE -/- had augmented AAA development and low doses of rosuvastatin can induce HO-1 expression in aortic tissue and suppress AAA progression Yet et al. FASEB J. 2003; Azuma et al. Plos One 2016; Taaha et al. Arterioscler Thromb Vasc Biol 2010; Schillinger et al. Thromb Res. 2002

8 Role of HO-1 in the development of AAA- study design C57BL6xFVBN Male, 6 m.o. HO-1 +/+ HO-1 -/- USG BW [g] Morphology Histology Ang II doses or 2500 ng/kg/min

9 AAA appeared earlier in HO-1 +/+ mice Day 0 Day 7 Day 28 HO-1 +/+ Thrombus Stabilized thrombus HO-1 -/- mice developed aneurysm later and it was not accompanied by thrombus HO-1 -/- Aorta Aneurysm Aneurysm Aorta Aorta Aneurysm

10 Lack of HO-1 decreased the risk of aneurysms but made it more susceptible to rupture Ang II [2500ng/kg/min] for 28 days Saline for 28 days Ang II treated mice (all) Ang II 2500 ng/kg/min Ang II 1000 ng/kg/min HO-1 +/+ HO-1 -/- HO-1 -/- HO-1 +/+ HO-1 -/- mice had decreased frequncy of AAA, Incidence rate of aneurysms Incidence rate of AAA but (AAA+ increased aneurysms MA) incidence rate of AAA rupture WT=11/13 (85%) KO=5/11 (45%) WT= 8/9 (89%) KO=5/8 (62%) WT=3/4 (75%) KO=1/3 (33%) p=0.08 p>0.05 p>0.05 WT=11/13 (85%) KO=3/11 (27%) WT= 8/9 (89%) KO=3/8 (37%) WT=3/4 (74%) KO=0/3 (0%) p=0.01 p=0.049 p>0.05 Mortality due to AAA rupture WT=3/11 (27%) KO=2/3 (67%) WT=2/8 (25%) KO=2/3 (67%) WT=1/3 (33%) KO=0/0 (0%) p>0.05 p>0.05 p>0.05 P value- exact Fisher's test

11 Ang II caused a rapid change in blood pressure in HO-1 +/+ but not in HO-1 -/- mice *p<0.05; **p<0.01 two-way ANOVA

12 Ang II caused an increase in WBC in the HO-1 -/- mice but not in HO-1 +/+ mice

13 HO-1 -/- mice had higher level of lymphocytes and monocytes after Ang II compared to HO-1 +/+ mice

14 Ang II caused a dose-dependant influx of macrophages (F4/80 cells) into the aortic wall of HO-1 +/+ mice Mag. 20x Sham F4/80 F4/80; Hoe Ang II 1000ng (AAA) Ang II 2500ng (AAA with thrombus)

15 Mag. 20x Sham Higher dose of Ang II caused an influx of macrophages (F4/80 cells) into the aortic wall of HO-1 -/- mice F4/80 F4/80; Hoe Ang II 1000ng (Aneurysm in MA) Ang II 2500ng (AAA)

16 Conclusions Simvastatin treatment increase anti-inflammatory and antioxidative properties of aneurysmal tissue. Simvastatin treated patients had higher level of antioxidative HO-1 and GSH in AAA tissue. HO-1 may play an important role in AAA development in mice. HO-1 -/- mice were more resistant to AAA formation but more prone to rupture. HO-1 -/- mice had delayed increase in blood pressure after angiotensin II. HO-1 -/- mice had a tendency towards lower number of macrophages when AAA appeared.

17 Acknowledgement Department of Medical Biotechnology, UJ Prof. Józef Dulak Prof. Alicja Józkowicz Agnieszka Łoboda, PhD Agnieszka Jaźwa, PhD Neli Kachamakova-Trojanowska, PhD Karolina Bukowska-Strakova, PhD Urszula Florczyk, PhD Anna Grochot-Przęczek, PhD Magdalena Kozakowska, PhD Jacek Stępniewski, PhD Technical assistants Ewa Werner, MSc Karolina Hajduk, MSc Agnieszka Andrychowicz-Róg, MSc Joanna Uchto-Bajołek, MA Janusz Drebot, MSc Tomasz Hajduk Kinga Kleczek, MSc Dept. of Surgery Medical University of Vinna Prof. Ihor Huk Prof. Josif Nanobachvili Christoph Neumayer, PhD Christoph Domenig, PhD Markus Klinger, PhD Wolf Eilenberg, MD Dept. of Internal Medicine II, Medical University of Vinna Svitlana Demyanets, PhD Supported by the Fuga IV program of the National Science Centre (DEC-2015/16/S/NZ4/00040 to APP).

18 Oxidative stress in the pathogenesis of AAA LPS ROS Pro-inflammatory cytokines NF-kB Nrf2 SOD GSH/GSSG GST TNF-α IL-1β IL-6 MMP-9 MMP-2 ROS Decreasesd expression of Nrf2/ARE and lower GSH level (p<0.01) was found in patients with coronary artery disease. Nrf2 inhibition decreases expression of HO-1, NQO1 and TRx genes in VSMC. Piechota, Goraca J Physiol Pharmacol. 2011; Piechota et al. Pharmacol Rep. 2011; 18 Takashi et al. Arterioscler. Thromb. Vasc. Biol. 2013; Mozzini et al. Free Radic. Bioll. Med. 2014

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