Camille M. Balarini

Adipokines, diabetes and atherosclerosis: an inflammatory association.

Cardiovascular diseases can be considered the most important cause of death in diabetic population and diabetes can in turn increase the risk of cardiovascular events. Inflammation process is currently recognized as responsible for the development and maintenance of diverse chronic diseases, including diabetes and atherosclerosis. Considering that adipose tissue is an important source of adipokines, which may present anti and proinflammatory effects, the aim of this review is to explore the role of the main adipokines in the pathophysiology of diabetes and atherosclerosis, highlighting the therapeutic options that could arise from the manipulation of these signaling pathways both in humans and in translational models.

Mechanisms of Enhanced Vasoconstriction in the Mouse Model of Atherosclerosis: the Beneficial Effects of Sildenafil

Sildenafil ameliorates aortic relaxations in apolipoprotein E knockout (apoE) mice. Now, we tested the hypothesis that endothelial dysfunction (ED) in this model is characterized by contractile hyperresponsiveness to phenylephrine (PE) and that this abnormality may be repaired using sildenafil. The aortic rings were evaluated in apoE mice treated with sildenafil (apoE-sil, 40 mg/kg/day) and compared with apoE and wild-type (WT) mice administered with vehicle (veh). The apoE-veh mice exhibited an imbalance of nitric oxide and reactive oxygen species (NO/ROS) levels and an increased maximum response (Rmax, 20%) and sensitivity (7%) to PE, which were not modified by endothelial removal. Under the prostanoids blockade, vasocontraction was decreased more in apoE-veh (-37%) than in WT (-27%) and apoE-sil (-30%) mice. NADPH-oxidase blockade abolished the enhanced contractile responsiveness in apoE-veh (-33%), without effects in WT and apoE-sil groups. The atherosclerotic lesions and the imbalance of NO/ROS were reduced (40%) in apoE-sil mice. In conclusion, ED in apoE mice was characterized by decreased NO-bioavailability and contractile hyperresponsiveness, due to thromboxane and oxidative stress, and was normalized by sildenafil. The beneficial effects of this phosphodiesterase-5 inhibitor on ED and lipid deposition provide new insights for its use as adjuvant in the treatment of atherosclerosis.

Inhibition of phosphodiesterase 5 restores endothelial function in renovascular hypertension

BackgroundThe clipping of an artery supplying one of the two kidneys (2K1C) activates the renin-angiotensin (Ang) system (RAS), resulting in hypertension and endothelial dysfunction. Recently, we demonstrated the intrarenal beneficial effects of sildenafil on the high levels of Ang II and reactive oxygen species (ROS) and on high blood pressure (BP) in 2K1C mice. Thus, in the present study, we tested the hypothesis that sildenafil improves endothelial function in hypertensive 2K1C mice by improving the NO/ROS balance.Methods2K1C hypertension was induced in C57BL/6 mice. Two weeks later, they were treated with sildenafil (40 mg/kg/day, via oral) or vehicle for 2 weeks and compared with sham mice. At the end of the treatment, the levels of plasma and intrarenal Ang peptides were measured. Endothelial function and ROS production were assessed in mesenteric arterial bed (MAB).ResultsThe 2K1C mice exhibited normal plasma levels of Ang I, II and 1–7, whereas the intrarenal Ang I and II were increased (~35% and ~140%) compared with the Sham mice. Sildenafil normalized the intrarenal Ang I and II and increased the plasma (~45%) and intrarenal (+15%) Ang 1–7. The 2K1C mice exhibited endothelial dysfunction, primarily due to increased ROS and decreased NO productions by endothelial cells, which were ameliorated by treatment with sildenafil.ConclusionThese data suggest that the effects of sildenafil on endothelial dysfunction in 2K1C mice may be due to interaction with RAS and restoring NO/ROS balance in the endothelial cells from MAB. Thus, sildenafil is a promising candidate drug for the treatment of hypertension accompanied by endothelial dysfunction and kidney disease.

Granulocyte colony stimulating factor prevents kidney infarction and attenuates renovascular hypertension.

Background: G-CSF is a critical regulator of hematopoietic cell proliferation, differentiation and survival. It has been reported that G-CSF attenuates renal injury during acute ischemia-reperfusion. In this study we evaluated the effects of G-CSF on the renal and cardiovascular systems of 2K1C hypertensive mice. Methods: Male C57BL/6 mice were subjected to left renal artery clipping (2K1C) or sham operation and were then administered G-CSF (100 µg/kg/day) or vehicle for 14 days. Results: Arterial pressure was higher in 2K1C + vehicle animals than in 2K1C + G-CSF (150±5 vs. 129±2 mmHg, p<0.01, n=8). Plasma angiotensin I, II and 1-7 concentrations were significantly increased in 2K1C + Vehicle when compared to the normotensive Sham group. G-CSF prevented the increase of these vasoactive peptides. The clipped kidney/contralateral kidney weight ratio showed a less atrophy of the ischemic kidney in the treated group (0.50±0.02 vs. 0.66±0.01, p<0.05). The infarction area in the clipped kidney was completely prevented in 7 out of 8 2K1C + G-CSF mice. Administration of G-CSF protected the clipped kidney from apoptosis. Conclusion: Our data indicate that G-CSF prevents kidney infarction and markedly attenuates the increases in plasma angiotensin levels and hypertension in 2K1C mice, reinforcing the protective effect of G-CSF on kidney ischemia.

Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis.

The usefulness of selective inhibitors of phosphodiesterase 5 (PDE5) is well known, first for the treatment of male erectile dysfunction and more recently for pulmonary hypertension. The discovery that PDE5 is present in the systemic artery endothelium and smooth muscle cells led investigators to test the extra sexual effects of sildenafil, the first and most investigated PDE5 inhibitor, in diseases affecting the systemic arteries. Cumulative data from experimental and clinical studies have revealed beneficial effects of sildenafil on systemic arterial hypertension and its target organs, such as the heart, kidneys and vasculature. An important effect of sildenafil is reduction of hypertension and improvement of endothelial function in experimental models of hypertension and hypertensive subjects. Interestingly, in angiotensin-dependent hypertension, its beneficial effects on endothelial and kidney dysfunctions seem to at least in part be caused by its ability to decrease the levels of angiotensin II and increase angiotensin 1-7, in addition to improving nitric oxide bioavailability and diminishing reactive oxygen species. Another remarkable finding on the effects of sildenafil comes from studies in apolipoprotein E knockout mice, a model of atherosclerosis that closely resembles human atherosclerotic disease. In this review, we focus on the promising beneficial effects of sildenafil for treating systemic high blood pressure, especially resistant hypertension, and the endothelial dysfunction that is present in hypertension and atherosclerosis.

Inhibition of PDE5 Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats

Renal artery stenosis is frequently associated with resistant hypertension, which is defined as failure to normalize blood pressure (BP) even when combined drugs are used. Inhibition of PDE5 by sildenafil has been shown to increase endothelial function and decrease blood pressure in experimental models. However, no available study evaluated the baroreflex sensitivity nor autonomic balance in renovascular hypertensive rats treated with sildenafil. In a translational medicine perspective, our hypothesis is that sildenafil could improve autonomic imbalance and baroreflex sensitivity, contributing to lower blood pressure. Renovascular hypertensive 2-kidney-1-clip (2K1C) and sham rats were treated with sildenafil (45 mg/Kg/day) during 7 days. At the end of treatment, BP and heart rate (HR) were recorded in conscious rats after a 24-h-recovery period. Spontaneous and drug-induced baroreflex sensitivity and autonomic tone were evaluated; in addition, lipid peroxidation was measured in plasma samples. Treatment was efficient in increasing both spontaneous and induced baroreflex sensitivity in treated hypertensive animals. Inhibition of PDE5 was also capable of ameliorating autonomic imbalance in 2K1C rats and decreasing systemic oxidative stress. Taken together, these beneficial effects resulted in significant reductions in BP without affecting HR. We suggest that sildenafil could be considered as a promising alternative to treat resistant hypertension.

A Disintegrin and Metalloprotease 17 in the Cardiovascular and Central Nervous Systems.

ADAM17 is a metalloprotease and disintegrin that lodges in the plasmatic membrane of several cell types and is able to cleave a wide variety of cell surface proteins. It is somatically expressed in mammalian organisms and its proteolytic action influences several physiological and pathological processes. This review focuses on the structure of ADAM17, its signaling in the cardiovascular system and its participation in certain disorders involving the heart, blood vessels, and neural regulation of autonomic and cardiovascular modulation.

Organic Nitrates: Past, Present and Future

Nitric oxide (NO) is one of the most important vasodilator molecules produced by the endothelium. It has already been established that NO/cGMP signaling pathway deficiencies are involved in the pathophysiological mechanisms of many cardiovascular diseases. In this context, the development of NO-releasing drugs for therapeutic use appears to be an effective alternative to replace the deficient endogenous NO and mimic the role of this molecule in the body. Organic nitrates represent the oldest class of NO donors that have been clinically used. Considering that tolerance can occur when these drugs are applied chronically, the search for new compounds of this class with lower tolerance potential is increasing. Here, we briefly discuss the mechanisms involved in nitrate tolerance and highlight some achievements from our group in the development of new organic nitrates and their preclinical application in cardiovascular disorders.

Reactive Oxygen Species in the Paraventricular Nucleus of the Hypothalamus Alter Sympathetic Activity During Metabolic Syndrome

The paraventricular nucleus of the hypothalamus (PVN) contains heterogeneous populations of neurons involved in autonomic and neuroendocrine regulation. The PVN plays an important role in the sympathoexcitatory response to increasing circulating levels of angiotensin II (Ang-II), which activates AT1 receptors in the circumventricular organs (OCVs), mainly in the subfornical organ (SFO). Circulating Ang-II induces a de novo synthesis of Ang-II in SFO neurons projecting to pre-autonomic PVN neurons. Activation of AT1 receptors induces intracellular increases in reactive oxygen species (ROS), leading to increases in sympathetic nerve activity (SNA). Chronic sympathetic nerve activation promotes a series of metabolic disorders that characterizes the metabolic syndrome (MetS): dyslipidemia, hyperinsulinemia, glucose intolerance, hyperleptinemia and elevated plasma hormone levels, such as noradrenaline, glucocorticoids, leptin, insulin, and Ang-II. This review will discuss the contribution of our laboratory and others regarding the sympathoexcitation caused by peripheral Ang-II-induced reactive oxygen species along the subfornical organ and paraventricular nucleus of the hypothalamus. We hypothesize that this mechanism could be involved in metabolic disorders underlying MetS.

Developing New Organic Nitrates for Treating Hypertension: A Review

Nitric oxide (NO) is one of the most important vasodilator molecules produced by endothelium and presents plenty of cardiovascular actions. It has already been established that deficiency in NO/cGMP signaling pathway is involved in pathophysiological mechanisms of many cardiovascular diseases. In this context, the use of NOreleasing drugs appears to be an effective alternative to replace the deficient endogenous NO and mimic the role of this molecule in the body. Organic nitrates represent the oldest class of NO donors that have been clinically applied. Considering that tolerance can occur when these drugs are used chronically, the search for new compounds of this class with lower tolerance potential is increasing. Here we briefly discuss the mechanisms involved in nitrate tolerance and highlight some achievements from our group in the development of new organic nitrates and their preclinical application in cardiovascular disorders.