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Stroke is a leading cause of death and disability worldwide. Several mechanisms are involved in the pathogenesis of ischemic stroke (IS). The contributory role of the inflammatory and immunity processes was demonstrated both in vitro and in animal models, and was confirmed in humans. IS evokes an immediate inflammatory response that involves complex cellular and molecular mechanisms. All components of the innate and adaptive immunity systems are involved in several steps of the ischemic cascade. In the early phase, inflammatory and immune mechanisms contribute to the brain tissue damage, whereas, in the late phase, they participate to the tissue repair processes. In particular, damage-associated molecular patterns (DAMPs) appear critical for the promotion of altered blood brain barrier permeability, leukocytes infiltration, tissue edema and brain injury. Conversely, the activation of regulatory T lymphocytes (Tregs) plays protective effects. The identification of specific cellular/molecular elements belonging to the inflammatory and immune responses, contributing to the brain ischemic injury and tissue remodeling, offers the advantage to design adequate therapeutic strategies. In this article, we will present an overview of the knowledge on inflammatory and immunity processes in IS, with a particular focus on the role of DAMPs and leukocytes infiltration. We will discuss evidence obtained in preclinical models of IS and in humans. The main molecular mechanisms useful for the development of novel therapeutic approaches will be highlighted. The translation of experimental findings to the human disease is still a difficult step to pursue. Further investigations are required to fill up the existing gaps.

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.

The mitochondrial uncoupling protein 2 (UCP2) plays a protective function in the vascular disease of both animal models and humans. UCP2 downregulation upon high-salt feeding favors vascular dysfunction in knock-out mice, and accelerates cerebrovascular and renal damage in the stroke-prone spontaneously hypertensive rat. Overexpression of UCP2 counteracts the negative effects of high-salt feeding in both animal models. We tested in vitro the ability of UCP2 to stimulate autophagy and mitophagy as a mechanism mediating its protective effects upon high-salt exposure in endothelial and renal tubular cells. UCP2 silencing reduced autophagy and mitophagy, whereas the opposite was true upon UCP2 overexpression. High-salt exposure increased level of reactive oxygen species (ROS), UCP2, autophagy and autophagic flux in both endothelial and renal tubular cells. In contrast, high-salt was unable to induce autophagy and autophagic flux in UCP2-silenced cells, concomitantly with excessive ROS accumulation. The addition of an autophagy inducer, Tat-Beclin 1, rescued the viability of UCP2-silenced cells even when exposed to high-salt. In summary, UCP2 mediated the interaction between high-salt-induced oxidative stress and autophagy to preserve viability of both endothelial and renal tubular cells. In the presence of excessive ROS accumulation (achieved upon UCP2 silencing and high-salt exposure of silenced cells) autophagy was turned off. In this condition, an exogenous autophagy inducer rescued the cellular damage induced by excess ROS level. Our data confirm the protective role of UCP2 toward high-salt-induced vascular and renal injury, and they underscore the role of autophagy/mitophagy as a mechanism counteracting the high-salt-induced oxidative stress damage.

The natriuretic peptides (NPs) family, including a class of hormones and their receptors, is largely known for its beneficial effects within the cardiovascular system to preserve regular functions and health. The concentration level of each component of the family is of crucial importance to guarantee a proper control of both systemic and local cardiovascular functions. A fine equilibrium between gene expression, protein secretion and clearance is needed to achieve the final optimal level of NPs. To this aim, the regulation of gene expression and translation plays a key role. In this regard, we know the existence of fine regulatory mechanisms, the so-called epigenetic mechanisms, which target many genes at either the promoter or the 3′UTR region to inhibit or activate their expression. The gene encoding ANP ( NPPA ) is regulated by histone modifications, DNA methylation, distinct microRNAs and a natural antisense transcript ( NPPA - AS1 ) with consequent implications for both health and disease conditions. Notably, ANP modulates microRNAs on its own. Histone modifications of BNP gene ( NPPB ) are associated with several cardiomyopathies. The proBNP processing is regulated by miR30-GALNT1/2 axis. Among other components of the NPs family, CORIN, NPRA, NPRC and NEP may undergo epigenetic regulation. A better understanding of the epigenetic control of the NPs family will allow to gain more insights on the pathological basis of common cardiovascular diseases and to identify novel therapeutic targets. The present review article aims to discuss the major achievements obtained so far with studies on the epigenetic modulation of the NPs family.

Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. In recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. They have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. Importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. In the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans.

Stroke represents a main cause of death and permanent disability worldwide. In the attempt to develop targeted preventive and therapeutic strategies, several efforts were performed over the last decades to identify the specific molecular abnormalities preceding cerebral ischemia and neuronal death. In this regard, mitochondrial dysfunction, autophagy, and intracellular calcium homeostasis appear important contributors to stroke development, as underscored by recent pre-clinical evidence. Intracellular calcium (Ca2+) homeostasis is regulated, among other mechanisms, by the calcium sensor stromal interaction molecule 1 (STIM1) and calcium release-activated calcium modulator (ORAI) members, which mediate the store-operated Ca2+ entry (SOCE). The activity of SOCE is deregulated in animal models of ischemic stroke, leading to ischemic injury exacerbation. We found a different pattern of expression of few SOCE components, dependent from a STIM1 mutation, in cerebral endothelial cells isolated from the stroke-prone spontaneously hypertensive rat (SHRSP), compared to the stroke-resistant (SHRSR) strain, suggesting a potential involvement of this mechanism into the stroke predisposition of SHRSP. In this article, we discuss the relevant role of STIM1 in experimental stroke, as highlighted by the current literature and by our recent experimental findings, and the available evidence in the human disease. We also provide a glance on future perspectives and clinical implications of STIM1.

Heart failure is a major side effect of doxorubicin (DOX) treatment in patients with cancer. However, the mechanisms underlying the development of DOX-induced heart failure need to be addressed. This study aims to test whether the serine/threonine kinase MST1, a major Hippo pathway component, contributes to the development of DOX-induced myocardial injury. C57BL/6J WT mice and mice with cardiomyocyte-specific dominant-negative MST1 (kinase-dead) overexpression received three weekly injections of DOX, reaching a final cumulative dose of 18 mg/kg. Echocardiographic, histological and biochemical analyses were performed six weeks after the first DOX administration. The effects of MST1 inhibition on DOX-induced cardiomyocyte injury were also tested in vitro. MST1 signaling was significantly activated in cardiomyocytes in response to DOX treatment in vitro and in vivo. Wild-type (WT) mice treated with DOX developed cardiac dysfunction and mitochondrial abnormalities. However, these detrimental effects were abolished in mice with cardiomyocyte-specific overexpression of dominant-negative MST1 (DN-MST1) or treated with XMU-MP-1, a specific MST1 inhibitor, indicating that MST1 inhibition attenuates DOX-induced cardiac dysfunction. DOX treatment led to a significant downregulation of cardiac levels of SIRT3, a deacetylase involved in mitochondrial protection, in WT mice, which was rescued by MST1 inhibition. Pharmacological inhibition of SIRT3 blunted the protective effects of MST1 inhibition, indicating that SIRT3 downregulation mediates the cytotoxic effects of MST1 activation in response to DOX treatment. Finally, we found a significant upregulation of MST1 and downregulation of SIRT3 levels in human myocardial tissue of cancer patients treated with DOX. In summary, MST1 contributes to DOX-induced cardiomyopathy through SIRT3 downregulation.

Background A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2 /rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2 /rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes. Methods Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway. Results The TT genotype at NDUFC2/ rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/ rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height 2.7 (p = 0.010) after adjustment for covariates. In-vitro , the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway. Conclusions We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

The tricuspid annular plane systolic excursion/systolic pulmonary arterial pressure (TAPSE/sPAP) ratio is an echocardiographic estimation of the right ventricle to pulmonary artery (RV/PA) coupling, with a validated prognostic role in different clinical settings. Systemic sclerosis (SSc) patients without evident cardiovascular involvement frequently display subtle RV impairment. The amino-terminal atrial natriuretic peptide (NT-proANP) plasma level relates to SSc disease progression and mortality. We aimed to assess the prognostic value of the TAPSE/sPAP ratio and its relationship with NT-proANP plasma level in SSc patients without overt cardiovascular involvement. We retrospectively analysed 70 SSc consecutive patients, with no clinical evidence of cardiovascular involvement or pulmonary hypertension (PH), and 30 healthy controls (HC) in a retrospective, single-centre study. All SSc patients underwent recurrent clinical and echocardiographic assessments and NT-proANP plasma level was assessed at baseline. SSc-related cardiovascular events and deaths were extracted during a 6-year follow-up. The complete work-up for the diagnosis, treatment and management of PH performed along the 6 years of follow-up referred to the 2015 European Society of Cardiology guidelines. Systemic sclerosis patients showed lower TAPSE/sPAP ratio at baseline compared to HC [SSc median value = 0.71 mm/mmHg, (IQR 0.62-0.88) vs. HC median value = 1.00 mm/mmHg, (IQR 0.96-1.05); < 0.001]. Multivariable Cox analysis revealed TAPSE/sPAP ratio as an independent predictor for SSc-related cardiovascular events [HR = 3.436 (95% CI 1.577-7.448); = 0.002] and mortality [HR = 3.653 (95% CI 1.712-8.892); = 0.014]. The value of TAPSE/sPAP ratio < 0.7 mm/mmHg was identified as an optimal cut-off for predicting adverse outcomes ( < 0.001) by receiver operating characteristic (ROC) analyses. NT-proANP level significantly related to TAPSE/sPAP ratio ( = < 0.001). TAPSE/sPAP ratio combined with NT-proANP showed an overall significant prognostic role in this SSc population, confirmed by Kaplan-Meier analysis (Log rank < 0.001). The TAPSE/sPAP ratio, as an index of RV/PA coupling, is an affordable predictor of cardiovascular events and mortality in SSc and, combined with NT-proANP level, may improve the clinical phenotyping and prognostic stratification of SSc patients.

Trehalose, spermidine, nicotinamide, and polyphenols have been shown to display pro-autophagic and antioxidant properties, eventually reducing cardiovascular and ischemic complications. This study aimed to investigate whether a mixture of these components improves maximal walking distance (MWD) in peripheral artery disease (PAD) patients. Nitrite/nitrate (NOx), endothelin-1, sNOX2-dp, H2O2 production, H2O2 break-down activity (HBA), ATG5 and P62 levels, flow-mediated dilation (FMD), and MWD were evaluated in 20 PAD patients randomly allocated to 10.5 g of mixture or no-treatment in a single-blind study. The above variables were assessed at baseline and 60 days after mixture ingestion. Compared with baseline, mixture intake significantly increased MWD (+91%; p < 0.01) and serum NOx (+96%; p < 0.001), whereas it significantly reduced endothelin-1 levels (−30%, p < 0.01). Moreover, mixture intake led to a remarkable reduction in sNOX2dp (−31%, p < 0.05) and H2O2 (−40%, p < 0.001) and potentiated antioxidant power (+110%, p < 0.001). Finally, mixture ingestion restored autophagy by increasing ATG5 (+43%, p < 0.01) and decreasing P62 (−29%, p < 0.05). No changes in the above-mentioned variables were observed in the no-treatment group. The treatment with a mixture of trehalose, spermidine, nicotinamide, and polyphenols improves MWD in PAD patients, with a mechanism possibly related to NOX2-mediated oxidative stress downregulation and autophagic flux upregulation. Clinical Trial Registration unique identifier: NCT04061070.