Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: Focus on cell–matrix signaling

Della Corte, Alessandro; Quarto, Cesare; Bancone, Ciro; Castaldo, Clotilde; Di Meglio, Franca; Nurzynska, Daria; De Santo, Luca S.; De Feo, Marisa; Scardone, Michelangelo; Montagnani, Stefania; Cotrufo, Maurizio

doi:10.1016/j.jtcvs.2007.09.009

« Previous Next »The Journal of Thoracic and Cardiovascular Surgery
Volume 135, Issue 1 , Pages 8-18.e2, January 2008

Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: Focus on cell–matrix signaling

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-9, 2007.

Alessandro Della Corte, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
- PhD program, “Medical and Surgical Physiopathology of the Cardio-Respiratory System and Associated Biotechnologies,” Second University of Naples, Italy.
- Address for reprints: Alessandro Della Corte, MD, Via P. Neruda, 6, 81031 Aversa CE, Italy.
Cesare Quarto, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
- PhD program, “Medical and Surgical Physiopathology of the Cardio-Respiratory System and Associated Biotechnologies,” Second University of Naples, Italy.
Ciro Bancone, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
Clotilde Castaldo, MD
- Department of Biomorphological and Functional Sciences, “Federico II” University, Secondo Policlinico, Naples, Italy.
Franca Di Meglio, MD
- Department of Biomorphological and Functional Sciences, “Federico II” University, Secondo Policlinico, Naples, Italy.
Daria Nurzynska, MD
- Department of Biomorphological and Functional Sciences, “Federico II” University, Secondo Policlinico, Naples, Italy.
Luca S. De Santo, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
Marisa De Feo, MD, PhD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
Michelangelo Scardone, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy
Stefania Montagnani, MD
- Department of Biomorphological and Functional Sciences, “Federico II” University, Secondo Policlinico, Naples, Italy.
Maurizio Cotrufo, MD
- Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy

Received 1 May 2007; received in revised form 23 August 2007; accepted 20 September 2007. published online 12 November 2007.

Objective

The present study examined temporal and spatial patterns of extracellular matrix and smooth muscle cell changes in the ascending aorta with bicuspid and tricuspid aortic valve stenosis.

Methods

Wall specimens were retrieved from both the greater and the lesser curvature (“convexity” and “concavity”) of 14 nonaneurysmal and 12 aneurysmal aortas (aortic ratios 1.2 and 1.5, respectively) and from 3 heart donors (normal). Immunochemistry was performed for detection of apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling [TUNEL]-positive) and proliferating (Ki-67-positive) smooth muscle cells and for semiquantification of matrix proteins (collagens, fibronectin, tenascin, laminin). Co-immunoprecipitation assessed the extent of Bcl-2-modifying factor binding to Bcl-2, indicating a matrix-derived cytoskeleton-mediated proapoptotic signaling. Polymerase chain reaction allowed for quantification of messenger RNA expression for Bcl-2.

Results

In both bicuspid and tricuspid aneurysms, fibrillar collagens were reduced, whereas fibronectin and tenascin were increased compared with those in normal conditions. These matrix alterations were already evident in bicuspid nonaneurysmal aortas at the convexity, with significant elevation of apoptotic indexes (P = .02 bicuspid vs normal; P = .48 tricuspid vs normal). Apoptotic indexes correlated with aortic dimensions only in tricuspid aortas (P = .01). No significant increase in Ki-67 was found. Higher levels of Bcl-2-modifying factor-Bcl-2 binding were found in bicuspid nonaneurysmal aorta versus tricuspid (P = .03) and normal aortas (P = .01). Bcl-2 messenger RNA expression was reduced in the bicuspid aorta versus normal (P = .08).

Conclusions

Smooth muscle cell apoptosis with bicuspid aortic valve stenosis occurred before overt aortic dilation, mainly at the convexity, where wall stress is expectedly higher. In this setting, a matrix-dependent proapoptotic signaling was evidenced by increased Bcl-2-modifying factor-Bcl-2 binding. Stress-dependent bicuspid aortic valve matrix changes may trigger early apoptosis by inducing cytoskeletal rearrangement.

CTSNet classification: 26, 29, 35

Abbreviations and Acronyms: AI, apoptotic index, BAV, bicuspid aortic valve, Bmf, Bcl-2-modifying factor, DAPI, 4′,6-diamidino-2′-phenylindole, ECM, extracellular matrix, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, MMP, matrix metalloproteinases, mRNA, messenger RNA, PBS, phosphate-buffered saline, PCR, polymerase chain reaction, SMC, smooth muscle cell, TAV, tricuspid aortic valve, TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling