Pyrrolidine dithiocarbamate down-regulates vascular matrix metalloproteinases and ameliorates vascular dysfunction and remodelling in renovascular hypertension

Abstract

BACKGROUND AND PURPOSEMounting evidence implicates matrix metalloproteinase (MMP) in the vascular dysfunction and remodelling associated with hypertension. We tested the hypothesis that treatment with pyrrolidine dithiocarbamate (PDTC), which interferes with NF-kB-induced MMPs gene transcription, could exert antihypertensive effects, prevent MMP-2 and MMP-9 up-regulation, and protect against the functional alterations and vascular remodelling of two-kidney, one clip (2K1C) hypertension. EXPERIMENTAL APPROACHSham-operated or hypertensive rats were treated with vehicle or PDTC (100 mg·Kg) by gavage for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic rings were isolated to assess endothelium-dependent relaxations. Quantitative morphometry of structural alterations of the aortic wall was carried out in haematoxylin/eosin sections. Formation of vascular reactive oxygen species (ROS), and inducible (i) NOS and phosphorylated-p65 NF-kB subunit expression were measured in the aortas. MMP-2 and MMP-9 aortic levels and gelatinolytic activity were determined by gelatin and in situ zymography and by immunofluorescence. KEY RESULTSTreatment with PDTC attenuated the increases in SBP and prevented the endothelial dysfunction associated with 2K1C hypertension. Moreover, PDTC reversed the vascular aortic remodelling, the increases in aortic ROS levels and in iNOS and phosphorylated-p65 NF-kB expression found in 2K1C rats. These effects were associated with attenuation of 2K1C up-regulation of aortic MMP-2 and MMP-9 levels and gelatinolytic activity. CONCLUSION AND IMPLICATIONSThese findings suggest that PDTC down-regulates vascular MMPs and ameliorates vascular dysfunction and remodelling in renovascular hypertension, thus providing evidence supporting the suggestion that PDTC is probably a good candidate to be used to treat hypertension.

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase‐2 Up‐Regulation in Renovascular Hypertension

“…The rats in the 2K1C hypertension group were treated with water (2K1C vehicle) or PDTC (2K1C PDTC). The rats in sham-operated groups received water (sham vehicle) or the same dose of PDTC (Sham PDTC), which was given at 100 mg/kg/day by gavage [15], starting 2 weeks after the induction of 2K1C hypertension. PDTC treatment was maintained for 8 weeks.…”

“…Additionally, MMP-2 degrades intracellular proteins such as troponin-I [8], myosin light chain [9], a-actinin [10] and titin [11], thus contributing to cardiac dysfunction. Transgenic mice with increased MMP-2 expression in cardiomyocytes develop left and right ventricular enlargements and important cardiac dysfunction [12], whereas hearts from MMP-2 knockout mice have preserved cardiac function and morphology when submitted to pressure overload conditions [13,14].We have previously shown that hypertension-induced increases in vascular MMP activity can be down-regulated at transcriptional level by inhibiting nuclear factor kappaB (NFjB) with pyrrolidine dithiocarbamate (PDTC) [15]. However, while PTDC has been previously shown to reduce the progression of cardiac hypertrophy, an effect associated with inhibition of cardiac MMP-2 up-regulation [16], there is no study examining the cardiac benefits of treatment with PDTC in the 2-kidney, 1-clip (2K1C) hypertension model, which is clearly associated with enhanced MMP-2 cardiac expression and activity and left ventricular dysfunction/remodelling [17,18].…”

“…We have previously shown that hypertension-induced increases in vascular MMP activity can be down-regulated at transcriptional level by inhibiting nuclear factor kappaB (NFjB) with pyrrolidine dithiocarbamate (PDTC) [15]. However, while PTDC has been previously shown to reduce the progression of cardiac hypertrophy, an effect associated with inhibition of cardiac MMP-2 up-regulation [16], there is no study examining the cardiac benefits of treatment with PDTC in the 2-kidney, 1-clip (2K1C) hypertension model, which is clearly associated with enhanced MMP-2 cardiac expression and activity and left ventricular dysfunction/remodelling [17,18].…”

Inducible Nitric Oxide Synthase Inhibition as a Target for the Treatment of Vascular Dysfunction in Hypertension

“…2 Pyrrolidine dithiocarbamate has been used in experimental models of hypertension, resulting in decreased vascular iNOS upregulation and an associated amelioration of NO-dependent vasorelaxation and vascular remodeling. 4 Thus, the association of pyrrolidine dithiocarbamate to antihypertensive therapy should be considered, because it represents a preventive way to inhibit iNOS expression and the vascular dysfunction associated with its activity. Although pyrrolidine dithiocarbamate was shown to be safe in different doses and routes of administration in preclinical studies, 5 additional data on its safety in humans as well as on the mechanisms involved in its beneficial vascular effects are warranted.…”

Regular swimming exercise performed either before or after the induction of renovascular hypertension alleviates oxidative renal injury in rats

“…Following renal angioplasty plasma renin activity, plasma Ang II concentration, as well as serum malondialdehyde-modified lowdensity lipoprotein concentration and urinary 8-hydroxy-2'-deoxyguanosine excretion were decreased in these patients with RVH, verifying the involvement of oxidative stress in the ethiopathogenesis of RVH. Accordingly, several potent antioxidants were investigated to be used as antihypertensive agents and were shown to reduce blood pressure by improving baroreflex sensitivity, down-regulating vascular matrix metalloproteinases or scavenging the oxygen radicals that would inactivate vasodilatory action of nitric oxide (NO) (3,4,5). Similar to antioxidants, aerobic exercise training was shown to reduce oxidative stress and inflammation and to increase anti-oxidant defenses by enhancing the resistance against reactive oxygeninduced lipid peroxidation and DNA damage (6,7).Voluntary running exercise in spontaneously hypertensive rats was shown to reduce plasma renin activity and plasma renin concentration (8) and improve microcirculatory profile in different tissues (9,10), making exercise a recommended non-pharmacological treatment modality in hypertension (11,12).…”