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Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness  Kartik Balachandran, PhD, Marina A. Bakay,

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Presentation on theme: "Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness  Kartik Balachandran, PhD, Marina A. Bakay,"— Presentation transcript:

1 Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness  Kartik Balachandran, PhD, Marina A. Bakay, PhD, Jeanne M. Connolly, MS, Xuemei Zhang, MS, Ajit P. Yoganathan, PhD, Robert J. Levy, MD  The Annals of Thoracic Surgery  Volume 92, Issue 1, Pages (July 2011) DOI: /j.athoracsur Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

2 Fig 1 The effects of 72 hours of cyclic stretch and serotonin (5HT; 10−5M), fluox (10−6M), or combined treatment of 5HT + fluox on cell proliferation. (A)-(H) Representative photomicrographs (original magnification 40×) of bromodeoxyuridine (BrdU) immunostaining of porcine aortic valves (PAV). (A) Static PAV; (B) static PAV + 5HT; (C) static PAV + fluox; (D) static PAV + 5HT and fluox; (E) cyclic stretch PAV; (F) cyclic stretch PAV + 5HT; (G) cyclic stretch PAV + fluox; (H) cyclic stretch PAV + 5HT and fluox; (I) graph shows quantitative results of PAV BrdU immunostaining; n = 6 per group, mean ± SEM. Cell proliferation (BrdU-positive stained cells) was significantly affected by stretch (p = ), while 2-way analysis of variance regressions showed no significant change under static conditions with the addition of 5HT, fluox, or both fluox and 5HT. Cyclic stretch increased proliferation within treatment groups versus static (p < ), with relative fold changes of 15, 5, 1.3, and 3.5 for control, 5HT, fluox, and combined treatments, respectively. Regression analysis showed that only 5HT and combined 5HT + fluox achieved statistical significance, at *p = 0.04 and **p < , respectively. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

3 Fig 2 The effects of 72 hours of cyclic stretch and serotonin (5HT; 10−5M), fluox (10−6M), or combined treatment of 5HT + fluox on total collagen, immature synthesized collagen production, and total soluble glycosaminoglycans (sGAG) in porcine aortic valves (PAV). Graphs show results for PAV samples, n = 6, mean ± standard error of the mean. (A) Total collagen production in PAV was increased by cyclic stretch (p = ), and unchanged by 5HT, fluox, or their combination unless cyclic stress was also applied (p < ). With cyclic stretch, treatment of PAV with 5HT + fluox resulted in an average twofold increase over the other 3 cyclic stretched groups (**p < versus static); cyclic-stretch alone or fluox alone had lesser effects (*p = 0.007, θp = 0.01, respectively). (B) Immature collagen production per picrosirius red staining revealed a significantly increased proportion of newly synthesized collagen fibers with application of cyclic stretch (p = ), and 2-way analysis of variance (ANOVA) regressions revealed that the pharmacologic agents only had effect under cyclic stretch (p < ). The combination of 5HT + fluox and cyclic stretch produced the highest increase in immature collagen fibers (**p < ). (C) The sGAG content was determined in PAVs, and was increased by cyclic stretch (p = 0.017). As in (A) and (B) above, no statistically significant effect of pharmacologic agents was found without cyclic stretch. However, 2-way ANOVA regressions showed a positive effect of pharmacologic agents with cyclic-stretch (p = 0.002), and specifically that 5HT + fluox under cyclic stretched conditions resulted in increased sGAG in comparison to unstretched 5HT + fluox (27.3-fold increase; **p < 0.001). The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

4 Fig 3 Principal component analyses (PCA) gene expression array data from porcine aortic valves after static or cyclic stretch incubation, with two-dimensional graphical representation of the principal components without or with cotreatment with serotonin (5HT) (10−5M) + fluox (10−6M). The PCA revealed clustering of 2 major principal components, indicating that the comparison of static versus cyclic stretch conditions is the dominant factor determining dysregulation at the genetic level. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

5 Fig 4 (A) Representative Western blot of porcine aortic valve interstitial cell (PAVIC) results showed dose-dependent responses to serotonin (5HT) in extracellular signal-related kinase (ERK) phosphorylation (pERK1/2). (B) Representative Western blot of PAVIC results demonstrated that both K and SB41 (see abbreviations below) inhibit 5HT-induced pERK1/2. (Mitogen activated protein kinase [MEK] inhibitor = PD98059 (PD); 5HTR antagonists (human): 5HTR2A = ketanserin (K); 5HTR2B = SB (SB41); 5HTR2C = SB (SB53); 5HTR1A = WAY (W); 5HTR1B = GR55562 (GR); 5HTR1D = BRL5572 (BRL). The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

6 Fig 5 The serotonin receptor (5HTR) responsiveness is enhanced by cyclic stretch due to increased 5HTR2A and 2B receptor expression. Cyclic stretch also results in increased proliferation and collagen production. However, when cyclic stretch induced increased 5HTR expression is combined with maximally enhanced 5HTR signaling due to serotonin (5HT) addition with serotonin transporter (5HTT) inhibition, increased receptor responsiveness results in significantly greater increases in all remodeling endpoints. The Annals of Thoracic Surgery  , DOI: ( /j.athoracsur ) Copyright © 2011 The Society of Thoracic Surgeons Terms and Conditions

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