Chronic Kidney Disease with Mineral Bone Disorder and Vascular Calcification: An Overview.

Chronic kidney disease (CKD) is a global health issue with a rising prevalence, affecting 697.5 million people worldwide. It imposes a substantial burden, contributing to 35.8 million disability-adjusted life years (DALYs) and 1.2 million deaths in 2017. The mortality rate for CKD has increased by 41.5% between 1990 and 2017, positioning it as a significant cause of global mortality. CKD is associated with diverse health complications, impacting cardiovascular, neurological, nutritional, and endocrine aspects. One prominent complication is CKD-mineral and bone disorder (MBD), a complex condition involving dysregulation of bone turnover, mineralization, and strength, accompanied by soft tissue and vascular calcification. Alterations in mineral metabolism, including calcium, phosphate, parathyroid hormone (PTH), vitamin D, fibroblast growth factor-23 (FGF-23), and Klotho, play pivotal roles in CKD-MBD. These disturbances, observed early in CKD, contribute to the progression of bone disorders and renal osteodystrophy (ROD). Vascular calcification (VC) is a key component of CKD-MBD, accelerated by CKD. The pathophysiology involves complex processes in vascular smooth muscle cells and the formation of calciprotein particles (CPP). VC is closely linked to cardiovascular events and mortality, emphasizing its prognostic significance. Various serum markers and imaging techniques, including lateral plain X-ray, Kauppila Score, Adragao Score, and pulse wave velocity, aid in VC detection. Additionally, pQCT provides valuable information on arterial calcifications, offering an advantage over traditional scoring systems. CKD poses a substantial global health burden, and its complications, including CKD-MBD and VC, significantly contribute to morbidity and mortality. Understanding the intricate relationships between mineral metabolism, bone disorders, and vascular calcification is crucial for effective diagnosis and therapeutic interventions.

Role of Dickkopf-3 in Blood Pressure Regulation in Mice and Hypertensive Rats.

BACKGROUND: Dkk3 (Dickkopf-3) is a secreted glycoprotein known for its proapoptotic and angiogenic activity. The role of Dkk3 in cardiovascular homeostasis is largely unknown. Remarkably, the Dkk3 gene maps within a chromosome segment linked to the hypertensive phenotype in spontaneously hypertensive rats (SHR). METHODS: We used Dkk3-/- mice or stroke-resistant (sr) and stroke-prone (sp) SHR to examine the role of Dkk3 in the central and peripheral regulation of blood pressure (BP). We used lentiviral expression vector to rescue Dkk3 in knockout mice or to induce Dkk3 overexpression or silencing in SHR. RESULTS: Genetic deletion of Dkk3 in mice enhanced BP and impaired endothelium-dependent acetylcholine-induced relaxation of resistance arteries. These alterations were rescued by restoring Dkk3 expression either in the periphery or in the central nervous system (CNS). Dkk3 was required for the constitutive expression of VEGF (vascular endothelium growth factor), and the action of Dkk3 on BP and endothelium-dependent vasorelaxation was mediated by VEGF-stimulated phosphatidylinositol-3-kinase pathway, leading to eNOS (endothelial NO synthase) activation both in resistance arteries and the CNS. The regulatory function of Dkk3 on BP was confirmed in SHR stroke-resistant and SHR stroke-prone in which was blunted in both resistance arteries and brainstem. In SHR stroke-resistant, lentiviral expression vector-induced Dkk3 expression in the CNS largely reduced BP, whereas Dkk3 knock-down further enhanced BP. In SHR stroke-prone challenged with a hypersodic diet, lentiviral expression vector-induced Dkk3 expression in the CNS displayed a substantial antihypertensive effect and delayed the occurrence of stroke. CONCLUSIONS: These findings demonstrate that Dkk3 acts as peripheral and central regulator of BP by promoting VEGF expression and activating a VEGF/Akt (protein kinase B)/eNOS hypotensive axis.

Impact of a NDUFC2 Variant on the Occurrence of Acute Coronary Syndromes.

Background: Among several potential mechanisms, mitochondrial dysfunction has been proposed to be involved in the pathogenesis of coronary artery disease (CAD). A mitochondrial complex I deficiency severely impairs cardiovascular health and contributes to CAD development. Previous evidence highlighted a key role of NDUFC2, a subunit of complex I, deficiency in the increased occurrence of renal and cerebrovascular damage in an animal model of hypertension, and of juvenile ischemic stroke occurrence in humans. Furthermore, a significant decrease of NDUFC2 mRNA was detected in peripheral blood mononuclear cells from patients experiencing acute coronary syndrome (ACS). The T allele at NDUFC2/rs23117379 variant is known to associate with reduced gene expression and mitochondrial dysfunction. Objective: In the present study we tested the impact of the T/C NDUFC2/rs23117379 variant on occurrence of ACS in a prospective cohort of CAD patients (n = 260). Results: Hypertension, smoking habit, diabetes and hypercholesterolemia were present in a large proportion of patients. Non-ST-elevation myocardial infarction (NSTEMI) represented the most frequent type of ACS (44%, n = 115), followed by ST-elevation myocardial infarction (STEMI) (34%, n = 88) and unstable angina (22%, n = 57). The alleles/genotypes distribution for T/C at NDUFC2/rs23117379 revealed that the TT genotype was associated with a trend toward the development of ACS at an earlier age (TT 61 ± 12, CT 65 ± 12 and CC 66 ± 11 years; p = 0.051 after adjustment for gender, hypertension, smoking habit, diabetes and hypercholesterolemia) and with a significant predictive role for ACS recurrence (hazard ratio [HR]1.671; 95% confidence interval [CI], 1.138-2.472; p = 0.009). Conclusions: Our findings are consistent with a deleterious effect of NDUFC2 deficiency on acute coronary events predisposition and further support a role of the NDUFC2/rs23117379 variant as a genetic cardiovascular risk factor.

Importance of Echocardiography and Clinical "Red Flags" in Guiding Genetic Screening for Fabry Disease.

Introduction: Aim of this study was to evaluate, in a metropolitan area not already explored, the prevalence of Anderson-Fabry disease, by genetic screening, in patients with echocardiographic evidence of left ventricular hypertrophy (LVH) of unknown origin and "clinical red flags". Methods: From August 2016 to October 2017, all consecutive patients referring to our echo-lab for daily hospital practices with echocardiographic evidence of LVH of unknown origin in association with history of at least one of the classical signs and symptoms related to Fabry disease (FD) (neuropathic pain, anhidrosis/hypohidrosis, angiokeratomas, gastrointestinal problems, chronic kidney disease, or cerebrovascular complications) were considered eligible for the FD genetic screening program. Through dried blood spot testing, α-Galactosidase A (α-Gal A) activity and analysis of the GLA gene were performed. Results: Among 3,360 patients who underwent transthoracic echocardiography in our echo-lab during the study period, 30 patients (0.89%; 19 men, mean age 58 ± 18.2 years) were selected. FD was diagnosed in 3 (10%) unrelated patients. Three different GLA gene mutations were detected, one of them [mutation c.388A > G (p.Lys130Glu) in exon 3] never described before. Moreover, probands' familiar genetic screening allowed the identification of 5 other subjects affected by FD. Conclusion: In a metropolitan area not previously investigated, among patients with LVH of unknown origin associated with other "red flags," undergoing genetic screening, the prevalence of FD was very high (10%). Our results highlight the importance of an echocardiographic- and clinical-oriented genetic screening for FD in patients with uncommon cause of LVH.

A Novel Combination of High-Load Omega-3 Lysine Complex (AvailOm®) and Anthocyanins Exerts Beneficial Cardiovascular Effects.

Omega-3 fatty acids have been shown to exert several beneficial effects in the prevention of cardiovascular and cerebrovascular diseases. The objective of the present study was to analyze the effects of a novel high-load omega-3 lysine complex, AvailOm®, its related constituents and a novel mixture of AvailOm® with specific vasoactive anthocyanins on vascular function in mice resistance artery. Pressure myograph was used to perform vascular reactivity studies. Nitric oxide and oxidative stress were assessed by difluorofluorescein diacetate and dihydroethidium, respectively. Increasing doses of AvailOm® exerted a dose-response vasorelaxation via AMPK-eNOS-mediated signaling. Omega-3 Ethyl Ester was identified as the main bioactive derivative of AvailOm®, being capable of inducing vasorelaxant action to the same extent of entire product. The combination of AvailOm® with a mix of potent vasoactive anthocyanins (C3-glu + DP3-glu + Mal3-glu + Mal3-gal + PEO3-gal), strongly protected mesenteric arteries from vascular dysfunction and oxidative stress evoked by oxidized-LDL. These data demonstrate for the first time the direct effects of AvailOm® on resistance arteries. The evidence that the combination of specific vasoactive anthocyanins and AvailOm® further enhanced the vasculoprotective properties of these compounds, may offer new promising perspectives for preventing the onset of cardiovascular and cerebrovascular events.

Targeting the ASMase/S1P pathway protects from sortilin-evoked vascular damage in hypertension.

Sortilin has been positively correlated with vascular disorders in humans. No study has yet evaluated the possible direct effect of sortilin on vascular function. We used pharmacological and genetic approaches coupled with study of murine and human samples to unravel the mechanisms recruited by sortilin in the vascular system. Sortilin induced endothelial dysfunction of mesenteric arteries through NADPH oxidase 2 (NOX2) isoform activation, dysfunction that was prevented by knockdown of acid sphingomyelinase (ASMase) or sphingosine kinase 1. In vivo, recombinant sortilin administration induced arterial hypertension in WT mice. In contrast, genetic deletion of sphingosine-1-phosphate receptor 3 (S1P3) and gp91phox/NOX2 resulted in preservation of endothelial function and blood pressure homeostasis after 14 days of systemic sortilin administration. Translating these research findings into the clinical setting, we detected elevated sortilin levels in hypertensive patients with endothelial dysfunction. Furthermore, in a population-based cohort of 270 subjects, we showed increased plasma ASMase activity and increased plasma levels of sortilin, S1P, and soluble NOX2-derived peptide (sNOX2-dp) in hypertensive subjects, and the increase was more pronounced in hypertensive subjects with uncontrolled blood pressure. Our studies reveal what we believe is a previously unrecognized role of sortilin in the impairment of vascular function and in blood pressure homeostasis and suggest the potential of sortilin and its mediators as biomarkers for the prediction of vascular dysfunction and high blood pressure.

Measurement of the QT interval using the Apple Watch.

The inherited and acquired long QT is a risk marker for potential serious cardiac arrhythmias and sudden cardiac death. Smartwatches are becoming more popular and are increasingly used for monitoring human health. The present study aimed to assess the feasibility and reliability of evaluating the QT interval in lead I, lead II, and V2 lead using a commercially available Apple Watch. One hundred nineteen patients admitted to our Cardiology Division were studied. I, II, and V2 leads were obtained after recording a standard 12-lead ECG. Lead I was recorded with the smartwatch on the left wrist and the right index finger on the crown. Lead II was obtained with the smartwatch on the left lower abdomen and the right index finger on the crown. The V2 lead was recorded with the smartwatch in the fourth intercostal space left parasternal with the right index finger on the crown. There was agreement among the QT intervals of I, II, and V2 leads and the QT mean using the smartwatch and the standard ECG with Spearman's correlations of 0.886; 0.881; 0.793; and 0.914 (p < 0.001), respectively. The reliability of the QTc measurements between standard and smartwatch ECG was also demonstrated with a Bland-Altman analysis using different formulas. These data show that a smartwatch can feasibly and reliably assess QT interval. These results could have an important clinical impact when frequent QT interval monitoring is required.

Therapy with RAS inhibitors during the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) is caused by the novel coronavirus first identified in Wuhan, China. The global number of confirmed cases of COVID-19 has surpassed 28,285,700 with mortality that appears higher than for seasonal influenza. About 20% of COVID-19 patients have experienced cardiac involvement and myocardial infarction in patients infected with SARS-CoV-2 had a worse prognosis. Furthermore, the widespread use of antiviral drugs can be linked to a worsening of heart function. Arrhythmias and hypertension have also been reported in patients with Covid-19. On the other hand, previous cardiac diseases are present in 30% of patients infected with SARS-CoV-2. There is uncertainty in the use of ace inhibitors and angiotensin II (Ang II) antagonists in the COVID-19 era. The mechanism of action of SARS-CoV-2 has been elucidated. It has been demonstrated that angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the new coronavirus SARS-CoV-2 and it is required for host cell entry and subsequent viral replication. The effect of the SARS-CoV-2 infection is the downregulation of ACE2 that may contribute to the severity of lung pathologies as well as the cardiac function. ACE2, a homolog of ACE, is a monocarboxypeptidase that converts Ang II into angiotensin 1-7 (Ang 1-7) that with its vasodilatory, antifibrotic, antihypertrophic effects counterbalances the negative effects of Ang II. On the other hand, angiotensin-converting enzyme inhibitors (ACEi) and AT1R blockers have been shown to upregulate the expression of ACE2. Based on the mechanism of action of SARS-CoV-2, the use of renin angiotensin system (RAS) inhibitors was questioned although all scientific societies did not recommend discontinuation when clinically recommended. The BRACE CORONA, a phase 4, randomized study tested two strategies: temporarily stopping the ACE inhibitor/angiotensin receptor blockers (ARB) for 30 days versus continuing ACE inhibitors/ARBs in patients who were taking these medications chronically and were hospitalized with a confirmed diagnosis of COVID-19 was also discussed. Therefore, the goal of this review is to summarize recent laboratory and clinical investigations concerning the use of ACEi and ARBs during the COVID-19 pandemic. The available data, based also on a randomized trial, suggest that ACEIs or ARBs, when clinically indicated, should be regularly used in the COVID-19 era.

Fast-track ruling in/out SARS-CoV-2 infection with rapid 0/1.5 h molecular test in patients with acute coronary syndromes.

AIMS: Patients with acute coronary syndrome (ACS) often arrive in the catheterization (cath) lab directly from the field or an emergency department without an accurate triage for Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Although in the pandemic period the treatment in the cath laboratory of high-risk ACS should not be delayed because the operators wear special protection systems, the subsequent risk of contagion in a non-Covid coronary care unit could be high in the case of patients positive for SARS-CoV-2. METHODS: We tested the possibility of a fast-track protocol in 51 consecutive patients (mean age 65 ±â€Š12 years) transferred from spokes centres or from the field to our HUB centre and admitted to our coronary care unit (CCU). Once the patient had arrived in the cath lab, the nasopharyngeal swab was performed. The real-time PCR to extract RNA for SARS-CoV-2 detection was performed with an automated rapid molecular Xpert Xpress test. Meanwhile, coronary angiography or percutaneous coronary intervention was performed if necessary. RESULTS: In this fast-track protocol, the time to perform nasopharyngeal swab was 11 ±â€Š11 min; time spent to transport nasopharyngeal swab to the laboratory was 29 ±â€Š20 min; time to detect viral nucleic acid was 68 ±â€Š16 min. The overall time from the execution of nasopharyngeal swab to the result was 109 ±â€Š26 min. The results were immediately put into the hospital computer system and made readily available. Depending on the test result, patients were then transferred to the regular CCU or Covid area. CONCLUSION: This study demonstrates that 0-1.5 h fast-track triage for coronavirus disease 2019 (COVID 19) is feasible in patients with ACS. The execution of nasopharyngeal swab in the cath lab and its analysis with a rapid molecular test allows rapid stratification of SARS-CoV-2 infection.

Multichannel Electrocardiograms Obtained by a Smartwatch for the Diagnosis of ST-Segment Changes.

Importance: Acute coronary syndromes are the leading cause of death worldwide and the leading cause of disease burden in high-income countries. Quick and accurate diagnosis of acute coronary syndromes is essential to avoid fatal events, for timely intervention, and to improve the prognosis. Objective: To prospectively investigate the feasibility and accuracy of a smartwatch in recording multiple electrocardiographic (ECG) leads and detecting ST-segment changes associated with acute coronary syndromes compared with a standard 12-lead ECG. Design, Setting, and Participants: A commercially available smartwatch was used in 100 participants to obtain multiple-channel ECGs. The study was conducted from April 19, 2019, to January 23, 2020. Fifty-four patients with ST elevation myocardial infarction, 27 patients with non-ST elevation myocardial infarction, and 19 healthy individuals were included in the study. The watch was placed in different body positions to obtain 9 bipolar ECG tracings (corresponding to Einthoven leads I, II, and III and precordial leads V1-V6) that were compared with a simultaneous standard 12-lead ECG. Main Outcomes and Measures: The concordance among the results of the smartwatch and standard ECG recordings was assessed using the Cohen κ coefficient and Bland-Altman analysis. Results: Of the 100 participants in the study, 67 were men (67%); mean (SD) age was 61 (16) years. Agreement was found between the smartwatch and standard ECG for the identification of a normal ECG (Cohen κ coefficient, 0.90; 95% CI, 0.78-1.00), ST-segment elevation changes (Cohen κ coefficient, 0.88; 95% CI, 0.78-0.97), and non-ST-segment elevation changes (Cohen κ coefficient, 0.85; 95% CI, 0.74-0.96). In addition, the Bland-Altman analysis demonstrated agreement between the smartwatch and standard ECG to detect the amplitude of ST-segment changes (bias, -0.003; SD, 0.18; lower limit, -0.36; and upper limit, 0.36). Use of the smartwatch ECG for the diagnosis of normal ECG showed a sensitivity of 84% (95% CI, 60%-97%) and specificity of 100% (95% CI, 95%-100%); for ST elevation, sensitivity was 93% (95% CI, 82%-99%) and specificity was 95% (95% CI, 85%-99%); and for NSTE ECG alterations, sensitivity was 94% (95% CI, 81%-99%) and specificity was 92% (95% CI, 83%-97%). Conclusions and Relevance: The findings of this study suggest agreement between the multichannel smartwatch ECG and standard ECG for the identification of ST-segment changes in patients with acute coronary syndromes.

New Nutraceutical Combination Reduces Blood Pressure and Improves Exercise Capacity in Hypertensive Patients Via a Nitric Oxide-Dependent Mechanism.

Background High blood pressure (BP) has long been recognized as a major health threat and, particularly, a major risk factor for stroke, cardiovascular disease, and end-organ damage. However, the identification of a novel, alternative, integrative approach for the control of BP and cardiovascular protection is still needed. Methods and Results Sixty-nine uncontrolled hypertension patients, aged 40 to 68 years, on antihypertensive medication were enrolled in 2 double-blind studies. Forty-five were randomized to placebo or a new nutraceutical combination named AkP05, and BP, endothelial function, and circulating nitric oxide were assessed before and at the end of 4 weeks of treatment. Twenty-four patients were randomized to diuretic or AkP05 for 4 weeks and underwent a cardiopulmonary exercise test to evaluate the effects of AkP05 on functional capacity of the cardiovascular, pulmonary, and muscular systems. Vascular and molecular studies were undertaken on mice to characterize the action of the single compounds contained in the AkP05 nutraceutical combination. AkP05 supplementation reduced BP, improved endothelial function, and increased nitric oxide release; cardiopulmonary exercise test revealed that AkP05 increased maximum O2 uptake, stress tolerance, and maximal power output. In mice, AkP05 reduced BP and improved endothelial function, evoking increased nitric oxide release through the PKCα/Akt/endothelial nitric oxide synthase pathway and reducing reactive oxygen species production via NADPH-oxidase inhibition. These effects were mediated by synergism of the single compounds of AkP05. Conclusions This is the first study reporting positive effects of a nutraceutical combination on the vasculature and exercise tolerance in treated hypertensive patients. Our findings suggest that AkP05 may be used as an adjunct for the improvement of cardiovascular protection and to better control BP in uncontrolled hypertension.

T Cells Are Dominant Population in Human Abdominal Aortic Aneurysms and Their Infiltration in the Perivascular Tissue Correlates With Disease Severity.

Abdominal Aortic Aneurysm (AAA) is a major cause of cardiovascular mortality. Adverse changes in vascular phenotype act in concert with chronic inflammation to promote AAA progression. Perivascular adipose tissue (PVAT) helps maintain vascular homeostasis but when inflamed and dysfunctional, can also promote vascular pathology. Previous studies suggested that PVAT may be an important site of vascular inflammation in AAA; however, a detailed assessment of leukocyte populations in human AAA, their anatomic location in the vessel wall and correlation to AAA size remain undefined. Accordingly, we performed in depth immunophenotyping of cells infiltrating the pathologically altered perivascular tissue (PVT) and vessel wall in AAA samples at the site of maximal dilatation (n = 51 patients). Flow cytometry revealed that T cells, rather than macrophages, are the major leukocyte subset in AAA and that their greatest accumulations occur in PVT. Both CD4+ and CD8+ T cell populations are highly activated in both compartments, with CD4+ T cells displaying the highest activation status within the AAA wall. Finally, we observed a positive relationship between T cell infiltration in PVT and AAA wall. Interestingly, only PVT T cell infiltration was strongly related to tertiles of AAA size. In summary, this study highlights an important role for PVT as a reservoir of T lymphocytes and potentially as a key site in modulating the underlying inflammation in AAA.

PTX3: an inflammatory protein modulating ultrastructure and bioenergetics of human endothelial cells.

BACKGROUND: Pentraxin 3 (PTX3), an acute-phase inflammation protein produced by several cell types, has long been described as a possible biomarker for age-related cardiovascular and cerebrovascular diseases. Although several mechanisms of action have been identified to date in the vascular and immune systems, the direct effects of PTX3 on isolated endothelial cells at morphological and metabolic levels remain unknown. FINDINGS: PTX3 induced cytoplasmic vacuolization and dilution of mitochondrial matrix in isolated, human endothelial cells. Moreover, metabolic assays revealed that PTX3 increases respiratory capacity in support of mitochondrial function, and partially sustains the glycolytic pathway. CONCLUSIONS: PTX3 has, per se, a direct action on ultrastructural and bioenergetic parameters of isolated endothelial cells. This finding can be associated with our previous demonstration of a deleterious effect of PTX3 on the endothelial layer. More studies are needed to clearly demonstrate any direct correlation between these ultrastructural and bioenergetic changes with endothelial dysfunction, especially with regard to age-related cerebro- and cardio-vascular diseases.

Novel Potent Decameric Peptide of Spirulina platensis Reduces Blood Pressure Levels Through a PI3K/AKT/eNOS-Dependent Mechanism.

Considered as a superfood of the future, Spirulina platensis matrix has been extensively used because of its beneficial effect on the management of cardiovascular diseases. However, its nutraceutical properties, bioactive compounds, and molecular mechanisms are unknown. Here, we demonstrate that S platensis matrix processed in vitro by simulated gastrointestinal digestion induces direct endothelial nitric oxide (NO)-mediated vasorelaxation of resistance vessels in mice. To gain insight into the bioactive compounds responsible for this effect, we used a complex multistep peptidomic approach to fractionate the crude digest: of the 5 peptide fractions identified (A-E), only fraction E evoked vasorelaxation. High-resolution mass spectrometry-based screening revealed in E the presence of 4 main peptides (SP3-SP6 [spirulina peptides]), of which only SP6 (GIVAGDVTPI) exerted direct endothelium-dependent vasodilation of ex vivo vessels, an effect occurring via a PI3K (phosphoinositide-3-kinase)/AKT (serine/threonine kinase Akt) pathway converging on NO release. In vivo, administration of SP6 evoked a significant hemodynamic effect, reducing blood pressure, an action absent in eNOS (endothelial NO synthase)-deficient mice. Of note, although lower doses of SP6 had no hemodynamic effects, it still enhanced endothelial NO vasorelaxation. Finally, in an experimental model of arterial hypertension, SP6 exerted an antihypertensive effect, improving endothelial vasorelaxation associated with enhanced serum nitrite levels. Based on our results, this novel decameric peptide may extend the possible fields of application for spirulina-derived peptides and could be developed into a promising nonpharmacological approach for the containment of pathologies associated with vascular NO misregulation.

The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation.

Diabetes mellitus is a common disease that affects 3⁻5% of the general population in Italy. In some countries of northern Europe or in North America, it can even affect 6⁻8% of the population. Of great concern is that the number of cases of diabetes is constantly increasing, probably due to the increase in obesity and the sedentary nature of the population. According to the World Health Organization, in the year 2030 there will be 360 million people with diabetes, compared to 170 million in 2000. This has important repercussions on the lives of patients and their families, and on health systems that offer assistance to patients. In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet hyperaggregation, highlighting the main molecular mechanisms involved and the interconnections.

Hypertension: Focus on autoimmunity and oxidative stress.

Understanding the causal role of the immune and inflammatory responses in hypertension has led to questions regarding the links between hypertension and autoimmunity. Immune pathology in primary hypertension mimics several autoimmune mechanisms observed in the pathogenesis of systemic lupus erythematosus, psoriasis, systemic sclerosis, rheumatoid arthritis and periodontitis. More importantly, the prevalence of hypertension in patients with these autoimmune diseases is significantly increased, when compared to control populations. Clinical and epidemiological evidence is reviewed along with possible mechanisms linking hypertension and autoimmunity. Inflammation and oxidative stress are linked in a self-perpetuating cycle that significantly contributes to the vascular dysfunction and renal damage associated with hypertension. T cell, B cell, macrophage and NK cell infiltration into these organs is essential for this pathology. Effector cytokines such as IFN-γ, TNF-α and IL-17 affect Na+/H+ exchangers in the kidney. In blood vessels, they lead to endothelial dysfunction and loss of nitric oxide bioavailability and cause vasoconstriction. Both renal and vascular effects are, in part, mediated through induction of reactive oxygen species-producing enzymes such as superoxide anion generating NADPH oxidases and dysfunction of anti-oxidant systems. These mechanisms have recently become important therapeutic targets of novel therapies focused on scavenging oxidative (isolevuglandin) modification of neo-antigenic peptides. Effects of classical immune targeted therapies focused on immunosuppression and anti-cytokine treatments are also reviewed.

Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases.

Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases.