Paolo Poggio1, Paola Songia2, Donato Moschetta2, Vincenza Valerio3, Veronika Myasoedova2, Gianluca L Perrucci4, Giulio Pompilio5. 1. Centro Cardiologico Monzino IRCCS, Unità per lo Studio di Patologie Aortiche, Valvolari e Coronariche, Milan, Italy. Electronic address: Paolo.Poggio@cardiologicomonzino.it. 2. Centro Cardiologico Monzino IRCCS, Unità per lo Studio di Patologie Aortiche, Valvolari e Coronariche, Milan, Italy. 3. Centro Cardiologico Monzino IRCCS, Unità per lo Studio di Patologie Aortiche, Valvolari e Coronariche, Milan, Italy; Università degli Studi di Napoli Federico II, Dipartimento di Medicina Clinica e Chirurgia, Napoli, Italy. 4. Centro Cardiologico Monzino IRCCS, Unità di Medicina Rigenerativa e Biologia Vascolare, Milan, Italy. 5. Centro Cardiologico Monzino IRCCS, Unità di Medicina Rigenerativa e Biologia Vascolare, Milan, Italy; Università degli Studi di Milano, Dipartimento di Scienze Cliniche e di Comunità, Milan, Italy; Centro Cardioloigco Monzino IRCCS, Dipartimento di Chirurgia Cardiovascolare, Milan, Italy. Electronic address: Giulio.Pompilio@cardiologicomonzino.it.
Abstract
AIMS: Calcific aortic valve stenosis (CAVS) is the most frequent manifestation of aortic valve disease and the third leading cause of cardiovascular disease in the Western countries associated with significant morbidity and mortality. An active biological progression involving inflammation and oxidation leading to valve endothelial damage is considered a hallmark of the early stages of valve degeneration. However, tricuspid (TAV) and bicuspid (BAV) aortic valve deterioration are considered to differ only by shear stress. We hypothesized that endothelial cells (EC) derived from BAV and TAV patients have different miRNA expression patterns and thus distinct pathways could lead to endothelial damage in BAV than TAV patients. METHODS AND RESULTS: We isolated ECs from patients with bicuspid or tricuspid aortic valve, which underwent surgery due to CAVS. MiRNA expression profile by PCR revealed eight upregulated miRNAs between BAV and TAV ECs. Functional analysis identified that BAV ECs presented altered cellular response to oxidative stress and DNA damage stimulus via p53 and alteration in the intrinsic apoptotic signaling pathway. GPX3 and SRXN1 mRNA were express at lower levels in BAV compared to TAV ECs, leading to an increment of DNA double-strand breaks. BAV ECs had a sustained apoptosis activation when compared to TAV ECs. This difference was exacerbated by oxidative stress stimulus leading to a reduced survival rate but completely reverted by miR-328-3p inhibition. CONCLUSION: The present data showed molecular differences in oxidative stress susceptibility, DNA damage magnitude, and apoptosis induction between ECs derived from BAV and TAV patients.
AIMS: Calcific aortic valve stenosis (CAVS) is the most frequent manifestation of aortic valve disease and the third leading cause of cardiovascular disease in the Western countries associated with significant morbidity and mortality. An active biological progression involving inflammation and oxidation leading to valve endothelial damage is considered a hallmark of the early stages of valve degeneration. However, tricuspid (TAV) and bicuspid (BAV) aortic valve deterioration are considered to differ only by shear stress. We hypothesized that endothelial cells (EC) derived from BAV and TAV patients have different miRNA expression patterns and thus distinct pathways could lead to endothelial damage in BAV than TAV patients. METHODS AND RESULTS: We isolated ECs from patients with bicuspid or tricuspid aortic valve, which underwent surgery due to CAVS. MiRNA expression profile by PCR revealed eight upregulated miRNAs between BAV and TAV ECs. Functional analysis identified that BAV ECs presented altered cellular response to oxidative stress and DNA damage stimulus via p53 and alteration in the intrinsic apoptotic signaling pathway. GPX3 and SRXN1 mRNA were express at lower levels in BAV compared to TAV ECs, leading to an increment of DNA double-strand breaks. BAV ECs had a sustained apoptosis activation when compared to TAV ECs. This difference was exacerbated by oxidative stress stimulus leading to a reduced survival rate but completely reverted by miR-328-3p inhibition. CONCLUSION: The present data showed molecular differences in oxidative stress susceptibility, DNA damage magnitude, and apoptosis induction between ECs derived from BAV and TAV patients.