Lipoxin-mediated signaling: ALX/FPR2 interaction and beyond.

In the aftermath of tissue injury or infection, an efficient resolution mechanism is crucial to allow tissue healing and preserve appropriate organ functioning. Pro-resolving bioactive lipids prevent uncontrolled inflammation and its consequences. Among these mediators, lipoxins were the first described and their pro-resolving actions have been mainly described in immune cells. They exert their actions mostly through formyl-peptide receptor 2 (ALX/FPR2 receptor), a G-protein-coupled receptor whose biological function is tremendously complex, primarily due to its capacity to mediate variable cellular responses. Moreover, lipoxins can also interact with alternative receptors like the cytoplasmic aryl hydrocarbon receptor, the cysteinyl-leukotrienes receptors or GPR32, triggering different intracellular signaling pathways. The available information about this complex response mediated by lipoxins is addressed in this review, going over the different mechanisms used by these molecules to stop the inflammatory reaction and avoid the development of dysregulated and chronic pathologies.

The prognostic impact of SIGLEC5-induced impairment of CD8+ T cell activation in sepsis.

BACKGROUND: Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) is deemed necessary for effective sepsis management. Here, we evaluated the role of SIGLEC5 as an IC ligand and explored its potential as a biomarker for sepsis. METHODS: In vitro and in vivo assays were conducted to both analyse SIGLEC5's role as an IC ligand, as well as assess its impact on survival in sepsis. A multicentre prospective cohort study was conducted to evaluate the plasmatic soluble SIGLEC5 (sSIGLEC5) as a mortality predictor in the first 60 days after admission in sepsis patients. Recruitment included sepsis patients (n = 346), controls with systemic inflammatory response syndrome (n = 80), aneurism (n = 11), stroke (n = 16), and healthy volunteers (HVs, n = 100). FINDINGS: SIGLEC5 expression on monocytes was increased by HIF1α and was higher in septic patients than in healthy volunteers after ex vivo LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ T-cell proliferation. Administration of sSIGLEC5r (0.8 mg/kg) had adverse effects in mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels of septic patients were higher than HVs and ROC analysis revealed it as a mortality marker with an AUC of 0.713 (95% CI, 0.656-0.769; p < 0.0001). Kaplan-Meier survival curve showed a significant decrease in survival above the calculated cut-off (HR of 3.418, 95% CI, 2.380-4.907, p < 0.0001 by log-rank test) estimated by Youden Index (523.6 ng/mL). INTERPRETATION: SIGLEC5 displays the hallmarks of an IC ligand, and plasma levels of sSIGLEC5 have been linked with increased mortality in septic patients. FUNDING: Instituto de Salud Carlos III (ISCIII) and "Fondos FEDER" to ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), CDF (PI21/01178), RLR (FI19/00334) and JAO (CD21/00059).

Targeting the TWEAK-Fn14 pathway prevents dysfunction in cardiac calcium handling after acute kidney injury.

Heart and kidney have a closely interrelated pathophysiology. Acute kidney injury (AKI) is associated with significantly increased rates of cardiovascular events, a relationship defined as cardiorenal syndrome type 3 (CRS3). The underlying mechanisms that trigger heart disease remain, however, unknown, particularly concerning the clinical impact of AKI on cardiac outcomes and overall mortality. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are independently involved in the pathogenesis of both heart and kidney failure, and recent studies have proposed TWEAK as a possible therapeutic target; however, its specific role in cardiac damage associated with CRS3 remains to be clarified. Firstly, we demonstrated in a retrospective longitudinal clinical study that soluble TWEAK plasma levels were a predictive biomarker of mortality in patients with AKI. Furthermore, the exogenous application of TWEAK to native ventricular cardiomyocytes induced relevant calcium (Ca2+ ) handling alterations. Next, we investigated the role of the TWEAK-Fn14 axis in cardiomyocyte function following renal ischaemia-reperfusion (I/R) injury in mice. We observed that TWEAK-Fn14 signalling was activated in the hearts of AKI mice. Mice also showed significantly altered intra-cardiomyocyte Ca2+ handling and arrhythmogenic Ca2+ events through an impairment in sarcoplasmic reticulum Ca2+ -adenosine triphosphatase 2a pump (SERCA2a ) and ryanodine receptor (RyR2 ) function. Administration of anti-TWEAK antibody after reperfusion significantly improved alterations in Ca2+ cycling and arrhythmogenic events and prevented SERCA2a and RyR2 modifications. In conclusion, this study establishes the relevance of the TWEAK-Fn14 pathway in cardiac dysfunction linked to CRS3, both as a predictor of mortality in patients with AKI and as a Ca2+ mishandling inducer in cardiomyocytes, and highlights the cardioprotective benefits of TWEAK targeting in CRS3. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Partial Genetic Deletion of Klotho Aggravates Cardiac Calcium Mishandling in Acute Kidney Injury.

Acute kidney injury (AKI) is associated with an elevated risk of cardiovascular major events and mortality. The pathophysiological mechanisms underlying the complex cardiorenal network interaction remain unresolved. It is known that the presence of AKI and its evolution are significantly associated with an alteration in the anti-aging factor klotho expression. However, it is unknown whether a klotho deficiency might aggravate cardiac damage after AKI. We examined intracellular calcium (Ca2+) handling in native ventricular isolated cardiomyocytes from wild-type (+/+) and heterozygous hypomorphic mice for the klotho gene (+/kl) in which an overdose of folic acid was administered to induce AKI. Twenty-four hours after AKI induction, cardiomyocyte contraction was decreased in mice with the partial deletion of klotho expression (heterozygous hypomorphic klotho named +/kl). This was accompanied by alterations in Ca2+ transients during systole and an impairment of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) function in +/kl mice after AKI induction. Moreover, Ca2+ spark frequency and the incidence of Ca2+ pro-arrhythmic events were greater in cardiomyocytes from heterozygous hypomorphic klotho compared to wild-type mice after AKI. A decrease in klotho expression plays a role in cardiorenal damage aggravating cardiac Ca2+ mishandling after an AKI, providing the basis for future targeted approaches directed to control klotho expression as novel therapeutic strategies to reduce the cardiac burden that affects AKI patients.

Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings: JACC: CardioOncology State-of-the-Art Review.

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care. We acknowledge that there are many additional therapies that are of significance but were not topics of discussion at this symposium. We hope that through this symposium-based review we can highlight the knowledge gaps and clinical priorities to inform the design of future studies that aim to prevent and mitigate cardiovascular disease in cancer patients and survivors.

Quantitative Proteomics Analysis Reveals That Cyclooxygenase-2 Modulates Mitochondrial Respiratory Chain Complex IV in Cardiomyocytes.

The biochemical mechanisms of cell injury and myocardial cell death after myocardial infarction remain unresolved. Cyclooxygenase 2 (COX-2), a key enzyme in prostanoid synthesis, is expressed in human ischemic myocardium and dilated cardiomyopathy, but it is absent in healthy hearts. To assess the role of COX-2 in cardiovascular physiopathology, we developed transgenic mice that constitutively express functional human COX-2 in cardiomyocytes under the control of the α-myosin heavy chain promoter. These animals had no apparent phenotype but were protected against ischemia-reperfusion injury in isolated hearts, with enhanced functional recovery and diminished cellular necrosis. To further explore the phenotype of this animal model, we carried out a differential proteome analysis of wild-type vs. transgenic cardiomyocytes. The results revealed a tissue-specific proteomic profile dominated by mitochondrial proteins. In particular, an increased expression of respiratory chain complex IV proteins was observed. This correlated with increased catalytic activity, enhanced respiratory capacity, and increased ATP levels in the heart of COX-2 transgenic mice. These data suggest a new link between COX-2 and mitochondria, which might contribute to the protective cardiac effects of COX-2 against ischemia-reperfusion injury.

Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation.

Specialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.

The Aryl Hydrocarbon Receptor Ligand FICZ Improves Left Ventricular Remodeling and Cardiac Function at the Onset of Pressure Overload-Induced Heart Failure in Mice.

Adverse ventricular remodeling is the heart's response to damaging stimuli and is linked to heart failure and poor prognosis. Formyl-indolo [3,2-b] carbazole (FICZ) is an endogenous ligand for the aryl hydrocarbon receptor (AhR), through which it exerts pleiotropic effects including protection against inflammation, fibrosis, and oxidative stress. We evaluated the effect of AhR activation by FICZ on the adverse ventricular remodeling that occurs in the early phase of pressure overload in the murine heart induced by transverse aortic constriction (TAC). Cardiac structure and function were evaluated by cardiac magnetic resonance imaging (CMRI) before and 3 days after Sham or TAC surgery in mice treated with FICZ or with vehicle, and cardiac tissue was used for biochemical studies. CMRI analysis revealed that FICZ improved cardiac function and attenuated cardiac hypertrophy. These beneficial effects involved the inhibition of the hypertrophic calcineurin/NFAT pathway, transcriptional reduction in pro-fibrotic genes, and antioxidant effects mediated by the NRF2/NQO1 pathway. Overall, our findings provide new insight into the role of cardiac AhR signaling in the injured heart.

Cardiac protection induced by urocortin-2 enables the regulation of apoptosis and fibrosis after ischemia and reperfusion involving miR-29a modulation.

Urocortin-2 (Ucn-2) has demonstrated cardioprotective actions against myocardial ischemia-reperfusion (I/R) injuries. Herein, we explored the protective role of Ucn-2 through microRNAs (miRNAs) post-transcriptional regulation of apoptotic and pro-fibrotic genes. We determined that the intravenous administration of Ucn-2 before heart reperfusion in a Wistar rat model of I/R recovered cardiac contractility and decreased fibrosis, lactate dehydrogenase release, and apoptosis. The infusion of Ucn-2 also inhibited the upregulation of 6 miRNAs in revascularized heart. The in silico analysis indicated that miR-29a and miR-451_1∗ are predicted to target many apoptotic and fibrotic genes. Accordingly, the transfection of neonatal rat ventricular myocytes with mimics overexpressing miR-29a, but not miR-451_1∗, prevented I/R-induced expression of pro- and anti-apoptotic genes such as Apaf-1, Hmox-1, and Cycs, as well as pro-fibrotic genes Col-I and Col-III. We also confirmed that Hmox-1, target of miR-29a, is highly expressed at the mRNA and protein levels in adult rat heart under I/R, whereas, Ucn-2 abolished I/R-induced mRNA and protein upregulation of HMOX-1. Interestingly, a significant upregulation of Hmox-1 was observed in the ventricle of ischemic patients with heart failure, correlating negatively with the left ventricle ejection fraction. Altogether, these data indicate that Ucn-2, through miR-29a regulation, provides long-lasting cardioprotection, involving the post-transcriptional regulation of apoptotic and fibrotic genes.

The anti-aging factor Klotho protects against acquired long QT syndrome induced by uremia and promoted by fibroblast growth factor 23.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased propensity for arrhythmias. In this context, ventricular repolarization alterations have been shown to predispose to fatal arrhythmias and sudden cardiac death. Between mineral bone disturbances in CKD patients, increased fibroblast growth factor (FGF) 23 and decreased Klotho are emerging as important effectors of cardiovascular disease. However, the relationship between imbalanced FGF23-Klotho axis and the development of cardiac arrhythmias in CKD remains unknown. METHODS: We carried out a translational approach to study the relationship between the FGF23-Klotho signaling axis and acquired long QT syndrome in CKD-associated uremia. FGF23 levels and cardiac repolarization dynamics were analyzed in patients with dialysis-dependent CKD and in uremic mouse models of 5/6 nephrectomy (Nfx) and Klotho deficiency (hypomorphism), which show very high systemic FGF23 levels. RESULTS: Patients in the top quartile of FGF23 levels had a higher occurrence of very long QT intervals (> 490 ms) than peers in the lowest quartile. Experimentally, FGF23 induced QT prolongation in healthy mice. Similarly, alterations in cardiac repolarization and QT prolongation were observed in Nfx mice and in Klotho hypomorphic mice. QT prolongation in Nfx mice was explained by a significant decrease in the fast transient outward potassium (K+) current (Itof), caused by the downregulation of K+ channel 4.2 subunit (Kv4.2) expression. Kv4.2 expression was also significantly reduced in ventricular cardiomyocytes exposed to FGF23. Enhancing Klotho availability prevented both long QT prolongation and reduced Itof current. Likewise, administration of recombinant Klotho blocked the downregulation of Kv4.2 expression in Nfx mice and in FGF23-exposed cardiomyocytes. CONCLUSION: The FGF23-Klotho axis emerges as a new therapeutic target to prevent acquired long QT syndrome in uremia by minimizing the predisposition to potentially fatal ventricular arrhythmias and sudden cardiac death in patients with CKD.

Interplay between mineral bone disorder and cardiac damage in acute kidney injury: from Ca2+ mishandling and preventive role of Klotho in mice to its potential mortality prediction in human.

Biomarkers of mineral bone disorders (MBD) including phosphorus, fibroblast growth factor (FGF)-23 and Klotho are strongly altered in patients with acute kidney injury (AKI) who have high cardiac outcomes and mortality rates. However, the crosslink between MBD and cardiac damage after an AKI episode still remains unclear. We tested MBD and cardiac biomarkers in an experimental AKI model after 24 or 72 hours of folic acid injection and we analyzed structural cardiac remodeling, intracellular calcium (Ca2+) dynamics in cardiomyocytes and cardiac rhythm. AKI mice presented high levels of FGF-23, phosphorus and cardiac troponin T and exhibited a cardiac hypertrophy phenotype accompanied by an increase in systolic Ca2+ release 24 hours after AKI. Ca2+ transients and contractile dysfunction were reduced 72 hours after AKI while diastolic sarcoplasmic reticulum Ca2+ leak, pro-arrhythmogenic Ca2+ events and ventricular arrhythmias were increased. These cardiac events were linked to the activation of the calcium/calmodulin-dependent kinase II pathway through the increased phosphorylation of ryanodine receptors and phospholamban specific sites after AKI. Cardiac hypertrophy and the altered intracellular Ca2+ dynamics were prevented in transgenic mice overexpressing Klotho after AKI induction. In a translational retrospective longitudinal clinical study, we determined that combining FGF-23 and phosphorus with cardiac troponin T levels achieved a better prediction of mortality in AKI patients at hospital admission. Thus, monitoring MBD and cardiac damage biomarkers could be crucial to prevent mortality in AKI patients. In this setting, Klotho might be considered as a new cardioprotective therapeutic tool to prevent deleterious cardiac events in AKI conditions.

Fibroblast Growth Factor-23-Klotho Axis in Cardiorenal Syndrome: Mediators and Potential Therapeutic Targets.

Cardiorenal syndrome (CRS) is a complex disorder that refers to the category of acute or chronic kidney diseases that induce cardiovascular disease, and inversely, acute or chronic heart diseases that provoke kidney dysfunction. There is a close relationship between renal and cardiovascular disease, possibly due to the presence of common risk factors for both diseases. Thus, it is well known that renal diseases are associated with increased risk of developing cardiovascular disease, suffering cardiac events and even mortality, which is aggravated in those patients with end-stage renal disease or who are undergoing dialysis. Recent works have proposed mineral bone disorders (MBD) as the possible link between kidney dysfunction and the development of cardiovascular outcomes. Traditionally, increased serum phosphate levels have been proposed as one of the main factors responsible for cardiovascular damage in kidney patients. However, recent studies have focused on other MBD components such as the elevation of fibroblast growth factor (FGF)-23, a phosphaturic bone-derived hormone, and the decreased expression of the anti-aging factor Klotho in renal patients. It has been shown that increased FGF-23 levels induce cardiac hypertrophy and dysfunction and are associated with increased cardiovascular mortality in renal patients. Decreased Klotho expression occurs as renal function declines. Despite its expression being absent in myocardial tissue, several studies have demonstrated that this antiaging factor plays a cardioprotective role, especially under elevated FGF-23 levels. The present review aims to collect the recent knowledge about the FGF-23-Klotho axis in the connection between kidney and heart, focusing on their specific role as new therapeutic targets in CRS.

Resolution-Based Therapies: The Potential of Lipoxins to Treat Human Diseases.

Inflammation is an a physiological response instead an essential response of the organism to injury and its adequate resolution is essential to restore homeostasis. However, defective resolution can be the precursor of severe forms of chronic inflammation and fibrosis. Nowadays, it is known that an excessive inflammatory response underlies the most prevalent human pathologies worldwide. Therefore, great biomedical research efforts have been driven toward discovering new strategies to promote the resolution of inflammation with fewer side-effects and more specificity than the available anti-inflammatory treatments. In this line, the use of endogenous specialized pro-resolving mediators (SPMs) has gained a prominent interest. Among the different SPMs described, lipoxins stand out as one of the most studied and their deficiency has been widely associated with a wide range of pathologies. In this review, we examined the current knowledge on the therapeutic potential of lipoxins to treat diseases characterized by a severe inflammatory background affecting main physiological systems, paying special attention to the signaling pathways involved. Altogether, we provide an updated overview of the evidence suggesting that increasing endogenously generated lipoxins may emerge as a new therapeutic approach to prevent and treat many of the most prevalent diseases underpinned by an increased inflammatory response.

Ca2+ mishandling in heart failure: Potential targets.

Ca2+ mishandling is a common feature in several cardiovascular diseases such as heart failure (HF). In many cases, impairment of key players in intracellular Ca2+ homeostasis has been identified as the underlying mechanism of cardiac dysfunction and cardiac arrhythmias associated with HF. In this review, we summarize primary novel findings related to Ca2+ mishandling in HF progression. HF research has increasingly focused on the identification of new targets and the contribution of their role in Ca2+ handling to the progression of the disease. Recent research studies have identified potential targets in three major emerging areas implicated in regulation of Ca2+ handling: the innate immune system, bone metabolism factors and post-translational modification of key proteins involved in regulation of Ca2+ handling. Here, we describe their possible contributions to the progression of HF.

Oxidized Low-Density Lipoprotein Associates with Ventricular Stress in Young Adults and Triggers Intracellular Ca2+ Alterations in Adult Ventricular Cardiomyocytes.

Oxidized low-density lipoprotein (oxLDL) is associated with cardiac damage and causes injury to multiple cell types. We aimed to investigate the role of oxLDL in ventricular stress. We first examined the association between circulating oxLDL and N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stress, in young subjects (30-50 years) with or without stable coronary artery disease (SCAD). oxLDL and NT-proBNP were significantly higher in subjects at high cardiovascular risk (CVR) than in subjects at low CVR and were associated independently of traditional CVR factors and C-reactive protein. Furthermore, the levels of oxLDL and NT-proBNP were significantly lower in subjects with SCAD than in peers at high CVR. To determine the intracellular mechanisms involved in the cardiac effects of oxLDL, we analyzed the in vitro effect of oxLDL on intracellular Ca2+ handling in adult rat ventricular cardiomyocytes using confocal microscopy. Acute challenge of adult ventricular cardiomyocytes to oxLDL reduced systolic Ca2+ transients and sarcoplasmic reticulum Ca2+ load. Moreover, diastolic spontaneous Ca2+ leak increased significantly after acute exposure to oxLDL. Thus, we demonstrate that oxLDL associates with NT-proBNP in young subjects, and can directly induce Ca2+ mishandling in adult ventricular cardiomyoyctes, predisposing cardiomyocytes to cardiac dysfunction and arrhythmogenicity.

Genetic Deletion of NOD1 Prevents Cardiac Ca2+ Mishandling Induced by Experimental Chronic Kidney Disease.

Risk of cardiovascular disease (CVD) increases considerably as renal function declines in chronic kidney disease (CKD). Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) has emerged as a novel innate immune receptor involved in both CVD and CKD. Following activation, NOD1 undergoes a conformational change that allows the activation of the receptor-interacting serine/threonine protein kinase 2 (RIP2), promoting an inflammatory response. We evaluated whether the genetic deficiency of Nod1 or Rip2 in mice could prevent cardiac Ca2+ mishandling induced by sixth nephrectomy (Nx), a model of CKD. We examined intracellular Ca2+ dynamics in cardiomyocytes from Wild-type (Wt), Nod1-/- and Rip2-/- sham-operated or nephrectomized mice. Compared with Wt cardiomyocytes, Wt-Nx cells showed an impairment in the properties and kinetics of the intracellular Ca2+ transients, a reduction in both cell shortening and sarcoplasmic reticulum Ca2+ load, together with an increase in diastolic Ca2+ leak. Cardiomyocytes from Nod1-/--Nx and Rip2-/--Nx mice showed a significant amelioration in Ca2+ mishandling without modifying the kidney impairment induced by Nx. In conclusion, Nod1 and Rip2 deficiency prevents the intracellular Ca2+ mishandling induced by experimental CKD, unveiling new innate immune targets for the development of innovative therapeutic strategies to reduce cardiac complications in patients with CKD.

Tumor stem cells fuse with monocytes to form highly invasive tumor-hybrid cells.

The 'cancer cell fusion' theory is controversial due to the lack of methods available to identify hybrid cells and to follow the phenomenon in patients. However, it seems to be one of the best explanations for both the origin and metastasis of primary tumors. Herein, we co-cultured lung cancer stem cells with human monocytes and analyzed the dynamics and properties of tumor-hybrid cells (THC), as well as the molecular mechanisms beneath this fusion process by several techniques: electron-microscopy, karyotyping, CRISPR-Cas9, RNA-seq, immunostaining, signaling blockage, among others. Moreover, mice models were assessed for in vivo characterization of hybrids colonization and invasiveness. Then, the presence of THCs in bloodstream and samples from primary and metastatic lesions were detected by FACS and immunofluorescence protocols, and their correlations with TNM stages established. Our data indicate that the generation of THCs depends on the expression of CD36 on tumor stem cells and the oxidative state and polarization of monocytes, the latter being strongly influenced by microenvironmental fluctuations. Highly oxidized M2-like monocytes show the strongest affinity to fuse with tumor stem cells. THCs are able to proliferate, colonize and invade organs. THC-specific cell surface signature CD36+CD14+PANK+ allows identifying them in matched primary tumor tissues and metastases as well as in bloodstream from patients with lung cancer, thus functioning as a biomarker. THCs levels in circulation correlate with TNM classification. Our results suggest that THCs are involved in both origin and spread of metastatic cells. Furthermore, they might set the bases for future therapies to avoid or eradicate lung cancer metastasis.

Innate Immune Receptors, Key Actors in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors-termed pattern recognition receptors (PRRs)-that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs.