Protective Effects of Novel Metal-Nonoates on the Cellular Components of the Vascular System

Abstract

At the cardiovascular level, nitric oxide (NO) controls smooth muscle functions, maintains vascular integrity, and exerts an antihypertensive effect. Metal-nonoates are a recently discovered class of NO donors, with NO release modulated through the complexation of the N-aminoethylpiperazine N-diazeniumdiolate ligand to metal ions, and thus representing a significant innovation with respect to the drugs traditionally used. In this study, we characterized the vascular protective effects of the most effective compound of this class, Ni(PipNONO)Cl, compared with the commercial N-diazeniumdiolate group derivate, diethylenetriamine/ nitric oxide (DETA/NO). Ni(PipNONO)Cl induced a concentrationdependent relaxation of precontracted rat aortic rings. The ED 50 was 0.67 mM, compared with 4.3 mM obtained with DETA/NO. When tested on cultured microvascular endothelial cells, Ni (PipNONO)Cl exerted a protective effect on the endothelium, promoting cell proliferation and survival in the picomolar range.

Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents

“…Indeed, stress insults as serum deprivation and ROSinduced cytotoxic mediators impair the eNOS/FGF-2 pathway [96][97][98]. Therapeutic strategies able to restore eNOS functioning and FGF-2 production and release have been developed and investigated, as activators of PKCepsilon isoform [99], novel NO donor drugs based on metallic centers [100], a VEGF mimetic peptide named QK [101] and the mitochondrial aldehyde dehydrogenase (ALDH2) activator, called Alda-1 [102] . ERK1/2 related p53 activation was responsible for doxorubicin induced caspase-3 cleavage.…”

Neuronal effects of a nickel-piperazine/NO donor complex in rodents

“…Metal-nonoates promoted proliferation of bovine coronary endothelial cells in a cGMP-dependent manner [64]. In a more recent study [41], the vascular protective effects of the most effective compound of this class, Ni(PipNONO)Cl, were described. We corroborated the protective effects of metal-nonoates on human endothelial cells of various origins, such as human umbilical vein endothelial cells (HUVECs) and human cardiac microvascular endothelial cells (HCMEC), of Ni(PipNONO)Cl.…”

“…Additional protective actions by Ni(PipNONO)Cl on vascular components were demonstrated as inhibition of smooth muscle cell migration and proliferation, and platelet aggregation. Reversion of an inflammatory phenotype [induced by interleukin (IL)-1ß] was obtained in the presence of the metal-nonoate [41].…”

Efficacy of AdipoDren® in Reducing Interleukin-1-Induced Lymphatic Endothelial Hyperpermeability

“…The expression of markers of inflammatory pathways (iNOS, eNOS, COX-2) and antioxidant/pro-oxidant enzymatic systems (SOD-1, catalase, p22 phox) was evaluated by Western blot as previously described [22,24]. Data are reported as arbitrary densitometric units (ADU) of the target protein with respect to β-actin used as the loading control.…”

“…After 24 h, the cells were washed and treated with the indicated stimuli. Immunofluorescence analysis was performed as previously reported [22,24] and fluorescence was quantified in digitalised images by using ImageJ software. …”