Natriuretic Peptides in the Cardiovascular System. Multifaceted Roles in Physiology, Pathology and Therapeutics

The natriuretic peptides (NPs) family includes a class of hormones and their receptors needed for the physiological control of cardiovascular functions. The discovery of NPs provided a fundamental contribution into our understanding of the physiological regulation of blood pressure, and of heart and kidney functions. NPs have also been implicated in the pathogenesis of several cardiovascular diseases (CVDs), including hypertension, atherosclerosis, heart failure, and stroke. A fine comprehension of the molecular mechanisms dependent from NPs and underlying the promotion of cardiovascular damage has contributed to improve our understanding of the molecular basis of all major CVDs. Finally, the opportunity to target NPs in order to develop new therapeutic tools for a better treatment of CVDs has been developed over the years. The current Special Issue of the Journal covers all major aspects of the molecular implications of NPs in physiology and pathology of the cardiovascular system, including NP-based therapeutic approaches

Resetting the neurohormonal balance in heart failure (HF). the relevance of the natriuretic peptide (NP) system to the clinical management of patients with HF

The natriuretic peptide (NP) system, which includes atrial natriuretic peptide, B-type natriuretic peptide, and C-type natriuretic peptide, has an important role in cardiovascular homeostasis, promoting a number of physiological effects including diuresis, vasodilation, and inhibition of the renin-angiotensin-aldosterone system. Heart failure (HF) is associated with defects in NP processing and synthesis, and there is a strong relationship between NP levels and disease state. NPs are useful biomarkers in HF, and their use in diagnosis and evaluation of prognosis is well established, particularly in patients with HF with reduced ejection fraction (HFrEF). There has also been interest in their use to guide disease management and therapeutic decision making. An understanding of NPs in HF has also resulted in interest in synthetic NPs for the treatment of HF and in treatments that target neprilysin, a protease that degrades NPs. A novel drug, the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (LCZ696), which simultaneously inhibits neprilysin and blocks the angiotensin II type I receptor, was shown to have a favorable efficacy and safety profile in patients with HFrEF and has been approved for use in such patients in Europe and the USA. In light of the development of treatments that target neprilysin and of recent data in relation to synthetic NPs, it is timely to review the current understanding of the role of NPs in HF and their use in diagnosis, evaluating prognosis and guiding treatment, as well as their place in HF therapy

Hypertension in the elderly. Which are the blood pressure threshold values?

Managing blood pressure is often difficult in the elderly, not only because of comorbidities, but also due to vascular remodelling and the changes in the renal and endocrine physiology. The structural and functional arterial modifications lead to impaired vessel’s compliance and increased systolic blood pressure (SBP), often with reduction of diastolic blood pressure (DBP)

Discovering a new role for the atrial natriuretic peptide: A novel risk factor for cardiovascular diseases

Atrial natriuretic peptide, a diuretic, natriuretic and vasorelaxant hormone, is also involved in the regulation of cardiovascular remodeling and it has been recently shown to be significantly associated with higher occurrence of cardiovascular diseases. In fact, high plasma ANP levels predict higher mortality rate for cardiovascular events. Moreover, ANP gene alterations are associated with higher risk of cardiovascular intermediate phenotypes, such as left ventricular hypertrophy, and of cardiovascular diseases, such as stroke and hypertension. Thus, the characterization of ANP plasma levels, and of ANP genotype for known mutations can be proposed as an informative component of the individual cardiovascular risk profile

The ATP synthase glycine zipper of the c subunits: from the structural to the functional role in mitochondrial biology of cardiovascular diseases

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Molecular Implications of natriuretic peptides in the protection from hypertension and target organ damage development

The pathogenesis of hypertension, as a multifactorial trait, is complex. High blood pressure levels, in turn, concur with the development of cardiovascular damage. Abnormalities of several neurohormonal mechanisms controlling blood pressure homeostasis and cardiovascular remodeling can contribute to these pathological conditions. The natriuretic peptide (NP) family (including ANP (atrial natriuretic peptide), BNP (brain natriuretic peptide), and CNP (C-type natriuretic peptide)), the NP receptors (NPRA, NPRB, and NPRC), and the related protease convertases (furin, corin, and PCSK6) constitute the NP system and represent relevant protective mechanisms toward the development of hypertension and associated conditions, such as atherosclerosis, stroke, myocardial infarction, heart failure, and renal injury. Initially, several experimental studies performed in different animal models demonstrated a key role of the NP system in the development of hypertension. Importantly, these studies provided relevant insights for a better comprehension of the pathogenesis of hypertension and related cardiovascular phenotypes in humans. Thus, investigation of the role of NPs in hypertension offers an excellent example in translational medicine. In this review article, we will summarize the most compelling evidence regarding the molecular mechanisms underlying the physiological and pathological impact of NPs on blood pressure regulation and on hypertension development. We will also discuss the protective effect of NPs toward the increased susceptibility to hypertensive target organ damage

Phytochemical Compounds and Protection from Cardiovascular Diseasesa. A State of the Art

Cardiovascular diseases represent a worldwide relevant socioeconomical problem. Cardiovascular disease prevention relies also on lifestyle changes, including dietary habits. The cardioprotective effects of several foods and dietary supplements in both animal models and in humans have been explored. It was found that beneficial effects are mainly dependent on antioxidant and anti-inflammatory properties, also involving modulation of mitochondrial function. Resveratrol is one of the most studied phytochemical compounds and it is provided with several benefits in cardiovascular diseases as well as in other pathological conditions (such as cancer). Other relevant compounds are Brassica oleracea, curcumin, and berberine, and they all exert beneficial effects in several diseases. In the attempt to provide a comprehensive reference tool for both researchers and clinicians, we summarized in the present paper the existing literature on both preclinical and clinical cardioprotective effects of each mentioned phytochemical. We structured the discussion of each compound by analyzing, first, its cellular molecular targets of action, subsequently focusing on results from applications in both ex vivo and in vivo models, finally discussing the relevance of the compound in the context of human diseases

Sacubitril/Valsartan. Potential Impact of ARNi "Beyond the Wall" of ACE2 on Treatment and Prognosis of Heart Failure Patients With Coronavirus Disease-19

From the beginning of the SARS-CoV-2 pandemia, the type 2 angiotensin-converting enzyme (ACE2), probably the most “unloved and neglected” member of the renin-angiotensin-aldosterone (RAAS) family, has attracted increasing attention since it has been shown as the cell receptor through which the virus enters into the cells (1). The physiological action of ACE2, a membrane protein expressed in the heart, lungs, kidneys, liver, and intestine, consists in degrading angiotensin II (Ang II) to angiotensin (1-7), a heptapeptide with a potent vasodilator function through the Mas receptor able to counterbalance the Ang II effects on vasoconstriction, sodium retention, and fibrosis (1). Previous studies have shown that Ang II type 1 receptor (AT1R) blockers (ARBs), ACE inhibitors (ACEI), and mineralocorticoid receptor antagonists (MRA) may up-regulate the expression of ACE2 both in acute and chronic settings of cardiovascular diseases (CVDs), such as hypertension, heart failure (HF) and myocardial infarction (1). These data have generated concern during the early phases of the pandemia, since it has been speculated that the increase in ACE2 level may have contributed to disease virulence and to adverse outcomes particularly in subjects affected by chronic coexisting conditions, namely hypertension, coronary artery disease, HF, and diabetes, who commonly received treatment with RAAS inhibitors and who were characterized by a worse clinical course (2). On the other hand, it has been observed that the binding between coronavirus and ACE2 leads to ACE2 downregulation, resulting in an unopposed production of Ang II by ACE, contributing to lung damage as a consequence of AT1R mediated inflammation, fibrosis, thrombosis, vasoconstriction, and increased vascular permeability. According to these findings, RAAS inhibitors and, in particular, ARBs may even protect against COVID-19 acute lung injury (1). As a matter of fact, epidemiological studies conducted in large populations of COVID-19 patients demonstrated that ARBs or ACE inhibitors had no association with a severe or fatal course of the diseas

Natriuretic peptides and cardiovascular damage in the metabolic syndrome. Molecular mechanisms and clinical implications

Natriuretic peptides are endogenous antagonists of vasoconstrictor and salt- and water-retaining systems in the body's defence against blood pressure elevation and plasma volume expansion, through direct vasodilator, diuretic and natriuretic properties. In addition, natriuretic peptides may play a role in the modulation of the molecular mechanisms involved in metabolic regulation and cardiovascular remodelling. The metabolic syndrome is characterized by visceral obesity, hyperlipidaemia, vascular inflammation and hypertension, which are linked by peripheral insulin resistance. Increased visceral adiposity may contribute to the reduction in the circulating levels of natriuretic peptides. The dysregulation of neurohormonal systems, including the renin-angiotensin and the natriuretic peptide systems, may in turn contribute to the development of insulin resistance in dysmetabolic patients. In obese subjects with the metabolic syndrome, reduced levels of natriuretic peptides may be involved in the development of hypertension, vascular inflammation and cardio vascular remodelling, and this may predispose to the development of cardiovascular disease. The present review summarizes the regulation and function of the natriuretic peptide system in obese patients with the metabolic syndrome and the involvement of altered bioactive levels of natriuretic peptides in the pathophysiology of cardiovascular disease in patients with metabolic abnormalities

The T2238C human atrial natriuretic peptide molecular variant and the risk of cardiovascular diseases

Atrial natriuretic peptide (ANP) is a cardiac hormone which plays important functions to maintain cardio-renal homeostasis. The peptide structure is highly conserved among species. However, a few gene variants are known to fall within the human ANP gene. The variant rs5065 (T2238C) exerts the most substantial effects. The T to C transition at the 2238 position of the gene (13-23% allele frequency in the general population) leads to the production of a 30-, instead of 28-, amino-acid-long α-carboxy-terminal peptide. In vitro, CC2238/αANP increases the levels of reactive oxygen species and causes endothelial damage, vascular smooth muscle cells contraction, and increased platelet aggregation. These effects are achieved through the deregulated activation of type C natriuretic peptide receptor, the consequent inhibition of adenylate cyclase activity, and the activation of Giα proteins. In vivo, endothelial dysfunction and increased platelet aggregation are present in human subjects carrying the C2238/αANP allele variant. Several studies documented an increased risk of stroke and of myocardial infarction in C2238/αANP carriers. Recently, an incomplete response to antiplatelet therapy in ischemic heart disease patients carrying the C2238/αANP variant and undergoing percutaneous coronary revascularization has been reported. In summary, the overall evidence supports the concept that T2238C/ANP is a cardiovascular genetic risk factor that needs to be taken into account in daily clinical practice