Salvatore Raffa1, Xiao Lan Diana Chin2, Rosita Stanzione3, Maurizio Forte3, Franca Bianchi3, Maria Cotugno3, Simona Marchitti3, Andrea Micaloni4, Giovanna Gallo5, Leonardo Schirone6, Giuliano Tocci7, Roberto Violini2, Maria Rosaria Torrisi1, Massimo Volpe7, Speranza Rubattu8. 1. Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Italy; Ultrastructural Pathology Lab., Medical Genetics and Advanced Cellular Diagnostics Unit, Sant'Andrea University Hospital, Rome, Italy. 2. Cardiology Unit, S. Camillo-Forlanini Hospital, Rome, Italy. 3. I.R.C.C.S. Neuromed, Pozzilli, Isernia, Italy. 4. Ultrastructural Pathology Lab., Medical Genetics and Advanced Cellular Diagnostics Unit, Sant'Andrea University Hospital, Rome, Italy. 5. Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Italy. 6. Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy. 7. Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Italy; I.R.C.C.S. Neuromed, Pozzilli, Isernia, Italy. 8. Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Italy; I.R.C.C.S. Neuromed, Pozzilli, Isernia, Italy. Electronic address: rubattu.speranza@neuromed.it.
Abstract
BACKGROUND: Deficiency of NADH dehydrogenase [ubiquinone], the mitochondrial complex I, represents an emerging mechanism of cardiovascular diseases. Ndufc2, a subunit of mitochondrial complex I, is involved in stroke development. We aimed to gain some insights on the role of Ndufc2 into acute coronary syndrome (ACS) through the assessment of its gene expression, along with that of anti-oxidant proteins and of mitochondrial function parameters, in circulating mononuclear cells (PBMCs) of ACS versus stable angina (SA) patients. The impact of NDUFC2 silencing in human endothelial and vascular smooth muscle cells was assessed in vitro. METHODS AND RESULTS: One hundred twenty-three patients presenting with SA (n = 41) or ACS (n = 82) were enrolled. PBMCs were used to assess the gene expression level of: NDUFC2, uncoupling protein 2 (UCP2), superoxide dysmutases 1 and 2 (SOD1, SOD2), levels of ROS and ATP. The mitochondrial dysfunction was assessed by cytofluorimetry; the structural damage by transmission electron microscopy. Cell viability, angiogenesis, markers of atherogenesis were evaluated in NDUFC2-silenced vascular cells. NDUFC2 mRNA level was significantly downregulated, along with UCP2, SOD1, SOD2 expression, in ACS patients. We found significant increases of ROS levels, reduced ATP levels, higher degree of mitochondrial structural damage and dysfunction in ACS patients. In vitro, NDUFC2 silencing favored mechanisms involved in atherogenesis and plaque vulnerability. CONCLUSIONS: A significant reduction of NDUFC2 expression is detected in ACS. In vitro, NDUFC2 silencing affects vascular cell viability and angiogenesis while stimulating the expression of markers of plaque rupture. Our observations suggest that these mechanisms may contribute to ACS development.
BACKGROUND:Deficiency of NADH dehydrogenase [ubiquinone], the mitochondrial complex I, represents an emerging mechanism of cardiovascular diseases. Ndufc2, a subunit of mitochondrial complex I, is involved in stroke development. We aimed to gain some insights on the role of Ndufc2 into acute coronary syndrome (ACS) through the assessment of its gene expression, along with that of anti-oxidant proteins and of mitochondrial function parameters, in circulating mononuclear cells (PBMCs) of ACS versus stable angina (SA) patients. The impact of NDUFC2 silencing in human endothelial and vascular smooth muscle cells was assessed in vitro. METHODS AND RESULTS: One hundred twenty-three patients presenting with SA (n = 41) or ACS (n = 82) were enrolled. PBMCs were used to assess the gene expression level of: NDUFC2, uncoupling protein 2 (UCP2), superoxide dysmutases 1 and 2 (SOD1, SOD2), levels of ROS and ATP. The mitochondrial dysfunction was assessed by cytofluorimetry; the structural damage by transmission electron microscopy. Cell viability, angiogenesis, markers of atherogenesis were evaluated in NDUFC2-silenced vascular cells. NDUFC2 mRNA level was significantly downregulated, along with UCP2, SOD1, SOD2 expression, in ACS patients. We found significant increases of ROS levels, reduced ATP levels, higher degree of mitochondrial structural damage and dysfunction in ACS patients. In vitro, NDUFC2 silencing favored mechanisms involved in atherogenesis and plaque vulnerability. CONCLUSIONS: A significant reduction of NDUFC2 expression is detected in ACS. In vitro, NDUFC2 silencing affects vascular cell viability and angiogenesis while stimulating the expression of markers of plaque rupture. Our observations suggest that these mechanisms may contribute to ACS development.