Copper reverses cardiomyocyte hypertrophy through vascular endothelial growth factor-mediated reduction in the cell size

Abstract

Previous studies have shown that dietary copper supplementation reversed heart hypertrophy induced by pressure overload in a mouse model. The present study was undertaken to understand the cellular basis of copper-induced regression of cardiac hypertrophy. Primary cultures of neonatal rat cardiomyocytes were treated with phenylephrine at a final concentration of 100 μM in cultures for 48 h to induce cellular hypertrophy. The hypertrophied cardiomyocytes were exposed to copper sulfate at a final concentration of 5 μM in cultures for additional 24 h. This copper treatment reduced the size of the hypertrophied cardiomyocytes, as measured by flow cytometry, protein content in cells, cell volume and cardiomyocyte hypertrophy markers including beta myosin heavy chain protein, skeletal alpha-actin, and atrial natriuretic peptide. Cell cycle analysis and cell sorting of p-histone-3 labeled cardiomyocytes indicated that cell division was not involved in the copper-induced regression of cardiomyocyte hypertrophy. Copper also inhibited PE-induced apoptosis, determined by a TUNEL assay. Because copper stimulates vascular endothelial growth factor (VEGF) production through activation of hypoxia-inducible transcription factor, an anti-VEGF antibody at a final concentration of 2 ng/ml in cultures was used and shown to blunt copper-induced regression of cell hypertrophy. Conversely, VEGF alone at a final concentration of 0.2 μg/ml reversed cell hypertrophy as the same as copper did. This study demonstrates that both copper and VEGF reduce the size of hypertrophied cardiomyocytes, and copper regression of cardiac hypertrophy is VEGF dependent.

Cardiac-Specific Overexpression of HIF-1α Prevents Deterioration of Glycolytic Pathway and Cardiac Remodeling in Streptozotocin-Induced Diabetic Mice

“…43 VEGF treatment of primary neonatal rat cardiomyocytes reduced phenylephrine-induced cell hypertrophy. 44 The data presented in the current study show that the prevention of cardiac myocyte hypertrophy and fibrosis by HIF-1␣ underscores a critical role of HIF-1␣ in transcriptional regulation of VEGF in cardiac remodeling in diabetic heart.…”

New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre?

“…Alkaline phosphatase cofactor; antioxidant and superoxide dismutase (SOD) cofactor (730,731) ; skeletal growth and maturation, and bone metabolism (732) ; chemical inactivator (46) ; formation of active carcinogenic compounds (93) ; Zn-binding compounds and cancer cell death (733) ; oesophagus cancer (734) ; Zn sensing receptor and cell signalling (735) ; immune functions (736) ; inflammatory diseases and cell signalling mechanisms (737) ; type 2 diabetes (738) ; food intake (739) Mn (569,700) : Antioxidant (740) ; metalloenzyme constituent and enzyme activation (569) ; bone health (732,741) ; manganese-SOD, NFkB activation and carcinogenic process (742) ; manganese-SOD and tumour growth (743) Cu (204,700) : Antioxidant (744) ; Cu-containing/binding proteins (569) ; bone health (732,745) ; central nervous system dysfunction (700) ; immune and cardiac dysfunctions (700,746,747) ; heart health (748,749) ; anti-cancer effect and DNA binding (750) ; risk of CHD (751,752) Se (204) :…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…Interestingly, the induction of chronic pressure overload in mice subjected to a constriction of the ascending aorta has been correlated to a plausibly defective copper homeostasis, since the oral administration of copper has been shown to easily reverse the pathology and promote angiogenesis through a higher biosynthesis and release of VEGF by the cardiomyocytes [27,286]. Accordingly, anti-VEGF antibodies blunted the copper-dependent recovery of damage.…”