Investigating the tumour promoting roles of complement membrane attack complex using global gene expression analysis.

Activation of complement and its terminal pathway leads to the formation and insertion of the membrane attack complex (MAC) in the membranes of target cells. Complement is activated in tumours as is clear from the presence of complement activation products in cancer tissues. Over-expression of membrane bound complement regulators on tumour cells together with endogenous recovery mechanisms restricts complement activity and results in escape from lytic killing; nevertheless, sublytic MAC deposition is not without consequence. Sublytic MAC assembly on nucleated cells causes cell activation, secretion of extracellular matrix and pro-inflammatory cytokines and may cause protection from apoptosis. Signalling of these events is unclear. The global effects of sublytic MAC were addressed in the murine colon carcinoma cell line (CT26) through the use of microarray technology. Cells were exposed to sublytic complement attack using pooled normal human serum (pNHS) and compared to MAC-inhibited controls generated using pNHS containing the C5 inhibitor OmCI. Total RNA was extracted at 0, 1 and 12 hours post-exposure and subjected to microarray analysis using the Illumina platform. Top statistically significant changes were then identified and a list of genes upregulated at both time points was uploaded to MetaCore and a gene network generated. From this a number of co-regulated genes which converged on the EGFR were highlighted. These were cxcl1, amphiregulin and matrix metalloproteinases (Mmp) 3 and 13. Both the top statistically significant and network derived genes were validated using qPCR. Changes in protein levels were then tested using western blot analyses for Mmp3 and Areg. Inhibition of the MEK/ERK, and to a lesser extent PI3K/Akt, signalling suppressed the gene upregulation that occurred in response to MAC but inhibition of p38 and JNK had no effect, implicating a MEK/ERK- PI3K co-activation. MAC deposition and not C5a/C5aR axis signalling was shown to be responsible for the mmp3 gene upregulation response. Identification of MAC-mediated events and the signalling pathways involved may provide insight into the mechanisms by which complement activation influences tumour growth. In particular the data suggest that sublytic MAC deposition might promote a gene expression response which pushes the cells to a more aggressive phenotype by the upregulation of proliferative, survival, invasion and migratory signals. This in turn will inform strategies that seek to harness complement or complement regulation in tumour immunotherapy

Mechanics of the tricuspid valve: from clinical diagnosis/treatment, in vivo and in vitro investigations, to patient-specific biomechanical modeling

Proper tricuspid valve (TV) function is essential to unidirectional blood flow through the right side of the heart. Alterations to the tricuspid valvular components, such as the TV annulus, may lead to functional tricuspid regurgitation (FTR), where the valve is unable to prevent undesired backflow of blood from the right ventricle into the right atrium during systole. Various treatment options are currently available for FTR; however, research for the tricuspid heart valve, functional tricuspid regurgitation, and the relevant treatment methodologies are limited due to the pervasive expectation among cardiac surgeons and cardiologists that FTR will naturally regress after repair of left-sided heart valve lesions. Recent studies have focused on (i) understanding the function of the TV and the initiation or progression of FTR using both in-vivo and in-vitro methods, (ii) quantifying the biomechanical properties of the tricuspid valve apparatus as well as its surrounding heart tissue, and (iii) performing computational modeling of the TV to provide new insight into its biomechanical and physiological function. This review paper focuses on these advances and summarizes recent research relevant to the TV within the scope of FTR. Moreover, this review also provides future perspectives and extensions critical to enhancing the current understanding of the functioning and remodeling tricuspid valve in both the healthy and pathophysiological states

Biaxial mechanical data of porcine atrioventricular valve leaflets

This dataset contains the anisotropic tissue responses of porcine atrioventricular valve leaflets to force-controlled biaxial mechanical testing. The set includes the first Piola-Kirchhoff Stress and the specimen stretches (λ) in both circumferential and radial tissue directions (C and R, respectively) for the mitral valve anterior and posterior leaflets (MVAL and MVPL), and the tricuspid valve anterior, posterior, and septal leaflets (TVAL, TVPL, and TVSL) from six porcine hearts at five separate force-controlled biaxial loading protocols. This dataset is associated with a companion journal article, which can be consulted for further information about the methodology, results, and discussion of this biaxial mechanical testing (Jett et al., https://doi.org/10.1016/j.jmbbm.2018.07.024)Support from the American Heart Association Scientist Development Grant (SDG) Award (16SDG27760143) is gratefully acknowledged. CHL was in part supported by the institutional start-up funds from the School of Aerospace and Mechanical Engineering (AME) and the research funding through the Faculty Investment Program from the Research Council at the University of Oklahoma (OU). SJ, RK, and DL were supported by the Mentored Research Fellowship from the Office of Undergraduate Research at OU. KK was supported by the Undergraduate Research Opportunities Program from the Honors College at OU. Open Access charges for this publication provided by University of Oklahoma Libraries Open Access Fund.Ye

Regional biaxial mechanical data of the mitral and tricuspid valve anterior leaflets

The collective data associated with this article presents the biaxial mechanical behavior for six smaller, delimited regions of the mitral valve and tricuspid valve anterior leaflets. Each data set consists of five columns of data, specifically: (i) biaxial testing protocol ID, (ii) circumferential stretch, (iii) radial stretch, (iv) circumferential membrane tension, and (v) radial membrane tension. For further elaboration regarding methodologies or results of the biaxial mechanical characterization please refer to the companion article Laurence, 2019.Support from the American Heart Association Scientist Development Grant (SDG) Award (16SDG27760143) is gratefully acknowledged. CHL was in part supported by the institutional start-up funds from the School of Aerospace and Mechanical Engineering (AME) and the research funding through the Faculty Investment Program from the Research Council at the University of Oklahoma (OU). DL, CR, and SJ were supported by the Mentored Research Fellowship from the Office of Undergraduate Research at OU. DL and CR were supported by the Undergraduate Research Opportunities Program from the Honors College at OU. We also acknowledge undergraduate researchers Jacob Richardson and Ryan Bodlak for their assistance with the biaxial mechanical testing.Ye

Biaxial mechanical data of porcine atrioventricular valve leaflets.

This dataset contains the anisotropic tissue responses of porcine atrioventricular valve leaflets to force-controlled biaxial mechanical testing. The set includes the first Piola-Kirchhoff Stress and the specimen stretches (λ) in both circumferential and radial tissue directions (C and R, respectively) for the mitral valve anterior and posterior leaflets (MVAL and MVPL), and the tricuspid valve anterior, posterior, and septal leaflets (TVAL, TVPL, and TVSL) from six porcine hearts at five separate force-controlled biaxial loading protocols. This dataset is associated with a companion journal article, which can be consulted for further information about the methodology, results, and discussion of this biaxial mechanical testing (Jett et al., in press) [1]

An investigation of the anisotropic mechanical properties and anatomical structure of porcine atrioventricular heart valves.

Valvular heart diseases are complex disorders, varying in pathophysiological mechanism and affected valve components. Understanding the effects of these diseases on valve functionality requires a thorough characterization of the mechanics and structure of the healthy heart valves. In this study, we performed biaxial mechanical experiments with extensive testing protocols to examine the mechanical behaviors of the mitral valve and tricuspid valve leaflets. We also investigated the effect of loading rate, testing temperatures, species (porcine versus ovine hearts), and age (juvenile vs adult ovine hearts) on the mechanical responses of the leaflet tissues. In addition, we evaluated the structure of chordae tendineae within each valve and performed histological analysis on each atrioventricular leaflet. We found all tissues displayed a characteristic nonlinear anisotropic mechanical response, with radial stretches on average 30.7% higher than circumferential stretches under equibiaxial physiological loading. Tissue mechanical responses showed consistent mechanical stiffening in response to increased loading rate and minor temperature dependence in all five atrioventricular heart valve leaflets. Moreover, our anatomical study revealed similar chordae quantities in the porcine mitral (30.5 ± 1.43 chords) and tricuspid valves (35.3 ± 2.45 chords) but significantly more chordae in the porcine than the ovine valves (p < 0.010). Our histological analyses quantified the relative thicknesses of the four distinct morphological layers in each leaflet. This study provides a comprehensive database of the mechanics and structure of the atrioventricular valves, which will be beneficial to development of subject-specific atrioventricular valve constitutive models and toward multi-scale biomechanical investigations of heart valve function to improve valvular disease treatments

An investigation of the anisotropic mechanical properties and anatomical structure of porcine atrioventricular heart valves

Valvular heart diseases are complex disorders, varying in pathophysiological mechanism and affected valve components. Understanding the effects of these diseases on valve functionality requires a thorough characterization of the mechanics and structure of the healthy heart valves. In this study, we performed biaxial mechanical experiments with extensive testing protocols to examine the mechanical behaviors of the mitral valve and tricuspid valve leaflets. We also investigated the effect of loading rate, testing temperatures, species (porcine versus ovine hearts), and age (juvenile vs adult ovine hearts) on the mechanical responses of the leaflet tissues. In addition, we evaluated the structure of chordae tendineae within each valve and performed histological analysis on each atrioventricular leaflet. We found all tissues displayed a characteristic nonlinear anisotropic mechanical response, with radial stretches on average 30.7% higher than circumferential stretches under equibiaxial physiological loading. Tissue mechanical responses showed consistent mechanical stiffening in response to increased loading rate and minor temperature dependence in all five atrioventricular heart valve leaflets. Moreover, our anatomical study revealed similar chordae quantities in the porcine mitral (30.5 ± 1.43 chords) and tricuspid valves (35.3 ± 2.45 chords) but significantly more chordae in the porcine than the ovine valves (p < 0.010). Our histological analyses quantified the relative thicknesses of the four distinct morphological layers in each leaflet. This study provides a comprehensive database of the mechanics and structure of the atrioventricular valves, which will be beneficial to development of subject-specific atrioventricular valve constitutive models and toward multi-scale biomechanical investigations of heart valve function to improve valvular disease treatments. This is the post print for the version of record: Jett, Samuel, Devin Laurence, Robert Kunkel, Anju R. Babu, Katherine Kramer, Ryan Baumwart, Rheal Towner, Yi Wu, and Chung-Hao Lee. "An investigation of the anisotropic mechanical properties and anatomical structure of porcine atrioventricular heart valves." Journal of the mechanical behavior of biomedical materials 87 (2018): 155-171. This post print is licensed CC BY-NC-ND and was retrieved from http://www.ou.edu/coe/ame/bbdl/publications.Ye