Targeting the renin-angiotensin system: what's new?

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.     

Diffuse endocrine system, neuroendocrine tumors and immunity: what's new?

During the last two decades, research into the modulation of immunity by the neuroendocrine system has flourished, unravelling significant effects of several neuropeptides, including somatostatin (SRIH), and especially cortistatin (CST), on immune cells. Scientists have learnt that the diffuse neuroendocrine system can regulate the immune system at all its levels: innate immunity, adaptive immunity, and maintenance of immune tolerance. Compelling studies with animal models have demonstrated that some neuropeptides may be effective in treating inflammatory disorders, such as sepsis, and T helper 1-driven autoimmune diseases, like Crohn's disease and rheumatoid arthritis. Here, the latest findings concerning the neuroendocrine control of the immune system are discussed, with emphasis on SRIH and CST. The second part of the review deals with the immune response to neuroendocrine tumors (NETs). The anti-NET immune response has been described in the last years and it is still being characterized, similarly to what is happening for several other types of cancer. In parallel with investigations addressing the mechanisms by which the immune system contrasts NET growth and spreading, ground-breaking clinical trials of dendritic cell vaccination as immunotherapy for metastatic NETs have shown in principle that the immune reaction to NETs can be exploited for treatment.     

Tissue-engineered blood vessels: alternative to autologous grafts?

Although vascular bypass grafting remains the mainstay for revascularization for ischemic heart disease and peripheral vascular disease, many patients do not have healthy vessels suitable for harvest. Thus, prosthetic grafts made of synthetic polymers were developed, but their use is limited to high-flow/low-resistance conditions because of poor elasticity, low compliance, and thrombogenicity of their synthetic surfaces. To fill this need, several laboratories have produced in vivo or in vitro tissue-engineered blood vessels using molds or prosthetic or biodegradable scaffolds, but each artificial graft has significant problems. Recently, conduits have been grown in the peritoneal cavity of the same animals in which they will be grafted, ensuring no rejection, in the short time of 2 to 3 weeks. Remodeling occurs after grafting such that the tissue is almost indistinguishable from native vessels. This conduit is derived from cells of bone marrow origin, opening new possibilities in vascular modeling and remodeling.     

Leptin as a link between the immune system and kidney‐related diseases: leading actor or just a coadjuvant?

Food intake and nutritional status modify the physiological responses of the immune system to illness and infection and regulate the development of chronic inflammatory processes, such as kidney disease. Adipose tissue secretes immune‐related proteins called adipokines that have pleiotropic effects on both the immune and neuroendocrine systems, linking metabolism and immune physiology. Leptin, an adipose tissue‐derived adipokine, displays a variety of immune and physiological functions, and participates in several immune responses. Here, we review the current literature on the role of leptin in kidney diseases, linking adipose tissue and the immune system with kidney‐related disorders. The modulation of this adipose hormone may have a major impact on the treatment of several immune‐ and metabolic‐related kidney diseases.     

How do blood vessels age? Mechanisms and clinical implications

Ageing is one of the most important cardiovascular risk factors. Vascular ageing is determined by genetic, mechanic and hemodynamic factors. The latter is strengthened by the fact that age-associated changes in capillaries and veins, vessels which are less prone to changes in pulsatility and blood pressure, are less pronounced or even absent. Age-related morphologic changes in large resistance vessels include an intima-media thickening, increased deposition of matrix substances, thus ultimately leading to a reduced compliance. Vascular ageing is mainly characterized by an impaired endothelium-dependent vasorelaxation. The expression of endothelial nitric oxide synthase (eNOS), producing vasodilatatory nitric oxide (NO), is markedly upregulated with increasing age. However, vasorelaxation is impaired, as the production of reactive oxygen species such as superoxide (O2-), concomitantly increases. NO and O2- react to form the powerful oxidant peroxynitrite (ONOO-). Peroxynitrite is known to initiate oxidative modification of proteins, including nitration of aromatic rings, thereby rendering functionally inactive certain regulatory proteins. Deposition of nitrated proteins is mainly found within endothelial mitochondria, suggesting that mitochondrial dysfunction plays a major role in the vascular ageing process. It yet remains to be shown whether oxidative stress, which is, according to the currently accepted "oxidative stress hypothesis", a key event of vascular ageing, can be pharmacologically prevented, e.g. by naturally occurring antioxidant vitamins. However, in a mammalian model of ageing, an unexpected accumulation of vitamin E was found to accumulate within the aortic wall. This may represent a self-regulatory adaptive mechanism to prevent age-associated oxidative stress. In contrast, ascorbic acid was found to decrease with increasing age. Eventually, it remains to be seen if vitamin C or other antioxidative substances may be useful therapies. Statins and ACE inhibitors are known to have effects on mechanisms interfering with the ageing process. Given the strong age-dependency of cardiovascular disease, the developments of therapies to delay vascular ageing might have enormous medical (and economic) consequences in the future.