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Dal Maso, Lucia (2014) Effetto del blocco del recettore AT1R dell'angiotensina II sullo stress ossidativo e sul signalling mediato dallo stress ossidativo nel danno cardiovascolare ed endoteliale del paziente iperteso. Studio ex vivo nell'uomo con approccio biologico molecolare. [Ph.D. thesis]

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Abstract (english)

High blood pressure is a major risk factor for cardiovascular disease, myocardial infarction, heart failure, kidney failure and peripheral vascular disease.
Oxidative stress, due to increased production of reactive oxygen species (ROS), plays an important pathophysiological role in the development of hypertension and its long-term complications, such as cardiovascular remodeling and atherosclerosis (Touyz RM et al, 2004).
Various risk factors (smoking, diabetes, increased LDL, as well as hypertension) lead to an increase of the redox state, resulting in endothelial dysfunction, increased expression of pro-inflammatory redox sensitive genes and activation of smooth muscle cells (Luft FC, 2001).
In hypertensive patients, the Renin-Angiotensin-Aldosterone system (RAAS) is activated and this causes an increase of Angiotensin (Ang II) production (Ruster C et al, 2006). Ang II causes vasoconstriction, increases total peripheral resistance and, consequently, blood pressure but at the same time strongly induces oxidative stress.
Ang II mediates its actions through two distinct receptors: AT1R (for which Ang II has more affinity) and AT2R (Dihn DT et al, 2001; Mehta PK et al, 2007; Calò LA et al, 2010). Many of the Ang II-related events are mediated via activation of the AT1R receptor followed by both a short term signaling, which causes vasoconstriction, and a long term signaling, which leads to vascular remodeling and atherosclerosis through the activation of NAPDH oxidase and consequently production of superoxide anion (O2-) (Griendling KK et al, 2000). Ang II signaling via AT2R stimulation has been suggested to counteract many actions mediated by AT1R inducing vasodilatation, anti-proliferation, cell differentiation, anti-apoptotic signals; it therefore has a role in the homeostatic counterbalance of an excessive stimulation of AT1R (Volpe et al, 2003; Zhuo et al, 2008; Yamamoto et al, 2008).
Oxidative stress is well recognized to play a crucial role in the pathogenic mechanisms of endothelial dysfunction. Endothelial dysfunction defines a complex molecular and biochemical picture of inflammatory, proliferative, structural and functional abnormalities of the vasculature. Endothelial progenitor cells (EPCs), derived from bone marrow, play an important role for the protection from these abnormalities (Hill JM et al, 2003), as they are able to repair the damaged endothelium, through a continuous process of re-endothelialization and/or neovascularization (Heiss C et al, 2005). In hypertension the number of circulating EPCs is reduced and their function is altered; this situation represents an additional risk factor in the development of cardiovascular events. It has been shown that Ang II and AngII-induced oxidative stress play a pivotal role in EPC status by accelerating the onset of their senescence, which, in turn, leads to impairment of their proliferative activity (Imanishi T et al, 2005). The calcitonin gene-related peptide (CGRP), instead, is a potent vasorelaxant, which prevents circulating EPC senescence and reverses AngII-induced senescence of EPC (Zhou Z et al, 2010).
The important role that oxidative stress plays in the cardiovascular remodelling and atherogenetic processes, that are observed in hypertension, has led researchers to investigate the potential pleiotropic effects of antihypertensive drugs on oxidative stress.
In particular, two drugs families are more intensive studied: ACE inhibitors (ACEIs) and the Ang II type 1 receptor blocker (ARBs) which both reduce RAAS activity.
Olmesartan Medoxomil, widely used in the treatment of hypertension, blocks specifically AT1R receptor and consequently its actions via short and long term signaling independently of the Ang II source. AngII is, then, available for binding to AT2R inducing vasodilatation, anti-inflammatory and antifibrotic effects and causing a dose-dependent reduction of blood pressure.
Furthemore, the treatment with Olmesartan has been shown to possess antioxidant-related effects such as reduction of the plasma levels 8-isoprostane, a marker of oxidative stress (Fliser D et al, 2005), and activation of Nitric Oxide (NO) system, through increase of eNOS phosphorylation (Oyama N et al, 2010; Kanematsu Y et al, 2006).
The aim of our study was, therefore, to evaluate a possible anti-oxidant and vasoprotective effect of the Olmesartan Medoxomil, in essential hypertensive patients, using a molecular biology approach.
The study was carried out at different times, using two cohorts of essential hypertensive patients with similar clinical features treated for six months with Olmesartan Medoxomil. On the first cohort of patients we analyzed markers of oxidative stress and cardiovascular remodelling-related pathways, as well as the level of oxidized LDL; on the second cohort of patients, we evaluated both the protein expression of HO-1, the plasma levels of CGRP and circulating EPCs number and senescence.
In particular, in the first phase of the study, we evaluated p22phox, subunit of NADPH oxidase, essential for the production of superoxide anion (O2-), and heme oxygenase-1 (HO-1), inducible isoform of HO, known to protect from oxidative stress. We also evaluated the state of phosphorylation of extracellular signal-regulated kinases (ERK1/2), an oxidative stress protein effector for cardiovascular remodeling, and the plasma level of the low-density lipoproteins (OxLDL), a plasma marker of oxidative stress, which is crucial in the development of arteries chronic inflammation at intima level.
In the second phase of the study, we evaluated the vasoprotective effects of Olmesartan, considering parameters such as: HO-1, potent anti-oxidant and anti-inflammatory protein, characterized by a strong effect on re-endothelialization, which is linked to its ability to increase the number and to reduce the senescence of circulating EPC; CGRP, peptide-stimulated by HO-1, that protect the endothelium and prevents circulating EPCs senescence. Moreover, were evaluated the number and survival of circulating EPCs.
The results of the first phase of the study, have demonstrated that Olmesartan Midoxomil, besides inducing blood pressure normalization in essential hypertensive patients since the third month of treatment, significantly reduced p22phox protein level after 3 months compared to baseline (0.71±0.26 vs 0,93±0.24 densitometric unit (d.u.,), p<0.001), and moreover significantly reduced p22phox at 6 months both compared to baseline (0.45±0.12 vs 0.93±0.24 d.u., p<0.001) and to 3 months (0.45±0.12 vs 0.71±0.26 d.u., p<0.02).
Olmesartan treatment also significantly decreased phosphorylated ERK 1/2 levels, both after 3 months compared to baseline (0.39±0.14 vs 0.56±0.11 d.u., p=0.001), and at 6 months compared to baseline (0.19±0.08 vs 0.56±0.11, d.u., p=0.001) and to 3 months (0.19±0.08 vs 0.39±0.14, d.u., p=0.001).
oxLDL plasma levels were significantly reduced after 6 months of treatment, both compared to baseline (171.92±61,83 vs 300.84±109.13 ng/ml, p=0.001), and to 3 months (171.92±61,83 vs 270.06±100.34 ng/ml, p=0.002), whereas at 3 months the reduction was not significant.
Furthermore, Olmesartan treatment caused a significant increase of HO-1 protein expression levels at 3 months of the therapy compared to baseline (1.10±0.19 vs 0.77±0.071 d.u., p=0.001) and at 6 months of the therapy compared to baseline (1.11±0.19 vs 0.77±0.071 d.u., p=0.001). There was no significant increase of HO-1 protein expression between 6 and 3 months of Olmesartan treatment (1.11±0.19 vs 1.10±0.19 d.u., p=ns).
In the second phase of the study, confirming the previously shown increase of HO-1, we found that Olmesartan significantly increased HO-1 protein level, both at 3 months compared to baseline (0.95±0,21 vs 0.81±0.21 d.u., p=0.031), and at 6 months compared to baseline (1.1±0.26 vs 0.81±0.21 d.u., p=0.001) and to 3 months (1.1±0.26 vs 0.95±0.21 d.u., p=0.01).
Moreover, we observed a significantly increase of CGRP plasma levels after 6 months of therapy, both compared to baseline (263.91±43.08 vs 198.81±51.98 pg/ml, p=0.001), and to 3 months (263.91±43.08 vs 218.97±41.13 pg/ml, p=0.03).
Circulating EPC number, defined by cell surface antigens CD34+KDR+, CD133+KDR+ e CD34+CD133+KDR+, increased after 6 months of Olmesartan treatment both compared to baseline (respectively, 112.89±53.44 vs 35.11±25.98, p=0.005; 107.60±37.09 vs 20.90±14.58, p=0.0001; 38.11±19.64 vs 3.67±3.61, p=0.0007) and compared to 3 months (respectively, 112.89±53.44 vs 59.11±35.30, p=0.002; 107.60±37.09 vs 49.50±45.20, p=0.003; 38.11±19.64 vs 15.78±18.59, p=0.0028).
Olmesartan significantly reduced EPC apoptosis, evaluated by gating on CD133+KDR+ cells events based on Annexin V expression, at 3 months compared to baseline (27.24± 9.64% vs 44.28 ± 12.38%, p<0.01) and further significantly reduced it at 6 months both compared to baseline (16.83±15.68% vs 44.28 ±12.38%, p<0.001) and to 3 months (16.83±15.68% vs 27.24±9.64%, p< 0.004) (Calò LA et al, 2014).
In conclusion, this study demonstrates Olmesartan’s inhibitory effect on oxidative stress and oxidative stress-related proteins involved in oxidative stress signaling in essential hypertensive patients. Moreover, it demonstrates a vasoprotective effect of Olmesartan via reduction of Ang II-mediated oxidative stress and increased CGRP-mediated improvement of endothelial dysfunction, likely due also to the increased number of circulating EPC and their improved survival/function.
In addition, our data provide a mechanistic rationale for the Olmesartan’s antioxidant and anti-inflammatory potential translation, in the long term, toward antiatherosclerotic and antiremodeling effects reported in clinical trials such as MORE (Stumpe KO et al 2007), OLIVUS (Hirohata A et al, 2010), EUTOPIA (Fliser D et al, 2004) e VIOS (Smith RD et al, 2006)

Abstract (italian)

L’ipertensione arteriosa è il più importante fattore di rischio per le malattie cardiovascolari, l’infarto del miocardio, lo scompenso cardiaco, l’insufficienza renale e le vasculopatie periferiche.
Lo stress ossidativo, dovuto all’aumentata produzione delle specie reattive all’ossigeno (ROS), svolge un importante ruolo fisiopatologico nello sviluppo dell’ipertensione arteriosa e delle sue complicanze a lungo termine, quali il rimodellamento cardiovascolare e l’aterosclerosi (Touyz RM et al, 2004).
Vari fattori di rischio (fumo, diabete, aumento di LDL, oltre che ipertensione) portano ad un aumento dello stato redox, determinando disfunzione endoteliale, aumento dell’espressione di geni pro-infiammatori redox sensibili ed attivazione delle cellule muscolari lisce (Luft FC, 2001).
In pazienti ipertesi, il sistema Renina-Angiotensina (RAAS) è attivato, causando un aumento di produzione dell’Angiotensina (Ang II) (Ruster C et al, 2006). L’Ang II, potente vasocostrittore (in grado di aumentare le resistenze periferiche totali e quindi la pressione arteriosa) è un potente induttore di stress ossidativo.
L’Ang II media le sue azioni attraverso due recettori distinti: AT1R e AT2R (Dihn DT et al, 2001; Mehta PK et al, 2007; Calò LA et al, 2010). La stimolazione del recettore AT1R, per il quale l’Ang II presenta maggiore affinità, determina sia vasocostrizione attraverso un signalling cellulare a breve termine ma anche rimodellamento vascolare e aterosclerosi attraverso un signalling a lungo termine che coinvolge l’attivazione dell’NADPH ossidasi, produttore di anione superossido (O2-) (Griendling KK et al, 2000). Il legame al recettore AT2R da parte dell’Ang II controbilancia gli effetti mediati dall’attivazione di AT1R, inducendo vasodilatazione, antiproliferazione, differenziazione cellulare, segnali antiapoptotici; esso ha quindi un ruolo omeostatico nel controbilanciare un eccesso di stimolazione di AT1R (Volpe et al, 2003; Zhuo et al, 2008; Yamamoto et al, 2008).
Lo stress ossidativo, è considerato uno dei meccanismi patogenetici fondamentali della disfunzione endoteliale. Per disfunzione endoteliale si intende un quadro molecolare e biochimico complesso che comprende infiammazione, proliferazione, anormalità strutturali e funzionali dei vasi. Le cellule progenitrici endoteliali (EPC) circolanti di derivazione midollare, svolgono un importante ruolo di protezione da queste alterazioni (Hill JM et al, 2003) in quanto sono in grado di riparare l’endotelio danneggiato attraverso un continuo processo di re-endotelializzazione e/o neovascolarizzazione (Heiss C et al, 2005).
Nell’ipertensione il numero di EPC circolanti è ridotto e la loro funzione è alterata; tale situazione rappresenta un ulteriore fattore di rischio nello sviluppo di eventi cardiovascolari. E’ stato dimostrato, infatti, che l’Ang II, che causa un aumento dello stress ossidativo, svolge un ruolo centrale nell’insorgenza dell’invecchiamento e nella inibizione della capacità proliferativa delle EPC circolanti (Imanishi T et al, 2005). Il calcitonin gene-related peptide (CGRP), invece, è un potente vasodilatatore, che previene l’invecchiamento delle EPC circolanti, indotto anche da Ang II (Zhou Z et al, 2010).
L’importante ruolo che gioca lo stress ossidativo nei processi di remodelling cardiovascolare ed aterogenesi che si osservano nell’ipertensione arteriosa, ha indotto i ricercatori a porre sempre maggior attenzione e ad investigare i potenziali effetti pleiotropici dei farmaci antiipertensivi sullo stress ossidativo.
I farmaci maggiormente studiati sono gli ACE inibitori (ACEIs) e i bloccanti il recettore AT1R dell'Angiotensina (ARBs), le due più importanti classi di farmaci che agiscono limitando l'attività del sistema renina-angiotensina-aldosterone (RAAS).
L’Olmesartan Medoxomil, bloccante il recettore AT1R dell’Ang II, ampiamente usato nel trattamento dell’ipertensione, blocca tutte le attività dell’Ang II mediate dal recettore AT1R, indipendentemente dall’origine e dalla via di sintesi dell’Ang II; l’ormone, perciò, si rende disponibile per il legame con il suo recettore AT2R, la cui stimolazione determina vasodilatazione, effetti antifibrotici e antinfiammatori e determina una riduzione, a lungo termine, dose-dipendente, della pressione arteriosa. Inoltre, è stato dimostrato che l’Olmesartan possiede attività antiossidante in quanto riduce i livelli plasmatici del marker di stress ossidativo 8-isoprostano (Fliser D et al, 2005), e attiva il sistema del monossido d’azoto (NO) attraverso un aumento della fosforilazione della eNOS (Oyama N et al, 2010; Kanematsu Y et al, 2006).
Con il nostro studio abbiamo valutato un possibile effetto antiossidante e vasoprotettivo dell’Olmesartan Medoxomil in pazienti ipertesi essenziali, utilizzando un approccio biologico molecolare.
Lo studio è stato effettuato in tempi differenti utilizzando due coorti di pazienti con caratteristiche cliniche simili trattati per 6 mesi con Olmesartan Medoximil. Sulla prima coorte sono stati analizzati markers di stress ossidativo e della pathway del rimodellamento cardiovascolare, oltre che i livelli di LDL ossidate; sulla seconda coorte di pazienti sono stati valutati oltre che l’espressione proteica di HO-1, i livelli palsmatici di CGRP e il numero e la sopravvivenza delle EPC circolanti.
In particolare, nella prima fase sono state valutate p22phox subunità della NADPH ossidasi essenziale per la produzione di anione superossido, ed Heme Oxigenase-1 (HO-1), isoforma inducibile di HO, in grado di proteggere dallo stress ossidativo. Abbiamo, inoltre, valutato lo stato di fosforilazione delle ERK, proteine effettrici dello stress ossidativo nel rimodellamento cardiovascolare, e lo stato di marker plasmatici di stress ossidativo come le lipoproteine ossidate a bassa densità (LDL ossidate), cruciali nello sviluppo della reazione infiammatoria cronica a livello della tonaca intima delle arterie.
Nella seconda fase dello studio abbiamo preso in considerazione gli effetti vasoprotettivi dell’Olmesartan valutando parametri quali: HO-1, proteina che oltre ad avere una potente attività anti-ossidante ed anti-infiammatoria, è contraddistinta da un potente effetto favorente la re-endotelializzazione, giustificato dalla sua capacità di aumentare il numero e di ridurre l’invecchiamento di cellule progenitrici endoteliali (EPC) circolanti ed il CGRP, peptide stimolato dall’HO-1 che protegge l’endotelio e previene l’invecchiamento delle EPC circolanti mediato da Ang II. Inoltre, sono stati valutati il numero e la sopravvivenza delle EPC circolanti.
I risultati della prima fase hanno dimostrato come il farmaco Olmesartan, oltre a normalizzare la pressione arteriosa in pazienti ipertesi essenziali già a 3 mesi di terapia, ha ridotto significativamente i livelli di espressione proteica di p22phox già a 3 mesi di terapia rispetto al basale (rispettivamente 0.71±0.26 vs 0.93±0.24 unità densitometriche (u.d.), p<0.001), riduzione che è risultata significativa anche a 6 mesi rispetto sia al basale (0.45±0.12 vs 0.93±0.24 u.d., p<0.001) che a 3 mesi (0.45±0.12 vs 0.71±0.26 u.d., p<0.02).
Il trattamento con Olmesartan ha ridotto significativamente anche i livelli di fosforilazione delle ERK 1/2 sia dopo 3 mesi rispetto al baseline (rispettivamente 0.39±0.14 vs 0.56±0.11 u.d., p=0.001) che a 6 mesi di terapia, rispetto al basale (0.19±0.08 vs 0.56±0.11, u.d., p=0.001) e rispetto a 3 mesi (0.19±0.08 vs 0.39±0.14 u.d., p=0.001).
I livelli di LDL ossidate sono risultati significativamente ridotti dopo 6 mesi di terapia, sia rispetto al basale (171.92±61.83 vs 300.84±109.13 ng/ml, p=0.001), che rispetto a 3 mesi (171.92±61.83 vs 270.06±100.34 ng/ml, p=0.002) mentre a 3 mesi rispetto al basale la riduzione non era significativa (270.06±100.34 vs 300.84±109.13 ng/ml, p=ns).
Il trattamento con Olmesartan ha, invece, determinato un significativo aumento dei livelli di espressione proteica di HO-1 rispetto al basale sia a 3 mesi di terapia (1.10±0.19 vs 0.77±0.071 u.d., p=0.001) che a 6 mesi (1.11±0.19 vs 0.77±0.071 u.d., p=0.001), mentre la variazione non è risultata significativa tra 3 e 6 mesi di trattamento (1.10±0.19 vs 1.11±0.19 u.d., p=ns).
Nella seconda parte dello studio, confermando quanto riscontrato precedentemente, il trattamento con Olmesartan ha incrementato significativamente i livelli di espressione proteica di HO-1 rispetto al basale sia a 3 mesi (0.95±0.21 vs 0.81±0.21 u.d., p=0.031) che a 6 mesi (1.1±0.26 vs 0.81±0.21 u.d., p=0.001) con un aumento significativo anche nel confronto tra 3 e 6 mesi (0.95±0.21 vs 1.1±0.26 u.d., p=0.01).
L’Olmesartan ha, inoltre, indotto un significativo aumento dei livelli plasmatici di CGRP dopo 6 mesi di terapia sia rispetto al basale (263.91±43.08 vs 198.81±51.98 pg/ml, p=0.001), che rispetto a 3 mesi (263.91±43.08 vs 218.97±41.13 pg/ml, p=0.03). Un aumento nel numero di EPC circolanti, espresse come CD34+KDR+, CD133+KDR+ e CD34+CD133+KDR+, è risultato significativo a 6 mesi di trattamento con Olmesartan sia rispetto al basale (rispettivamente 112.89±53.44 vs 35.11±25.98, p=0.005 per CD34+KDR+; 107.60±37.09 vs 20.90±14.58, p=0.0001 per CD133+KDR+; 38.11±19.64 vs 3.67±3.61, p=0.0007 per CD34+ CD133+KDR+) che a 3 mesi (112.89±53.44 vs 59.11±35.30, p=0.002 per CD34+KDR+; 107.60±37.09 vs 49.50±45.20, p=0.003 per CD133+KDR+; 38.11±19.64 vs 15.78±18.59, p=0.0028 per CD34+ CD133+KDR+).
L’apoptosi delle cellule EPC, valutata mediante analisi citofluorimetrica del legame tra annessina V e fosfatidilserina espressa sulle cellule CD133+KDR+, è risultata significativamente ridotta già a 3 mesi di trattamento con Olmesartan (27.24± 9.64% vs 44.28 ± 12.38%, p<0.01) e si è ulteriormente ridotta in modo significativo a 6 mesi sia rispetto al basale (16.83±15.68% vs 44.28 ±12.38%, p<0.001) che rispetto a 3 mesi (16.83±15.68 vs 27.24±9.64% %, p< 0.004) (Calò LA et al, 2014).
In conclusione, questo studio dimostra un effetto inibitorio dell’Olmesartan sullo stress ossidativo e sulle proteine correlate coinvolte nel signalling intracellulare dello stress ossidativo in pazienti con ipertensione essenziale. Inoltre, dimostra che l’Olmesartan possiede un effetto vasoprotettivo mediato dalla riduzione dello stress ossidativo indotto dall’Ang II e dall’aumento degli effetti benefici del CGRP sulla disfunzione endoteliale, dovuti anche all’aumento del numero delle EPC circolanti e della loro sopravvivenza/funzionalità.
I nostri dati, inoltre, forniscono un razionale meccanicistico dell’azione anti-ossidante, anti-infiammatoria e vasoprotettiva, forniscono il razionale meccanicistico agli effetti anti-aterosclerotici, antiinfiammatori e di anti-remodeling di Olmesartan riportati da trials clinici come MORE (Stumpe KO et al 2007), OLIVUS (Hirohata A et al, 2010), EUTOPIA (Fliser D et al, 2004) e VIOS (Smith RD et al, 2006)

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EPrint type:Ph.D. thesis
Tutor:Calò, Lorenzo A.
Data di deposito della tesi:28 January 2014
Anno di Pubblicazione:28 January 2014
Key Words:Angiotensina II/Angiotensin II; Stress Ossidativo/Oxidative Stress; Disfunzione Endoteliale/Endothelial Dysfunction; eme-ossigenasi-1/Heme-oxygenase-1;CGRP/CGRP; cellule progenitrici endoteliali circolanti/circulating endothelial progenitor cells.
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/14 Nefrologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:6442
Depositato il:03 Nov 2014 12:18
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