OBJECTIVE: This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mech...OBJECTIVE: This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mechanisms involved in sGC activator-induced vasodilation in human arteries. METHODS: sGC/PKG were stimulated by sodium nitroprusside (SNP) or the sGC activator cinaciguat. Mesenteric and intrarenal arteries from young and aged mice as well as from patients who underwent elective colon resection or nephrectomy were investigated by wire myography. Phosphorylation of the regulatory 20-kDa light-chain of myosin at serine 19 (MLC-S19) and targeting-subunit-of-myosin-phosphatase at threonine 853 and serine 668 (MYPT1-T853 and MYPT1-S668) were determined by Western blot. RESULTS: In murine vessels, SNP- and cinaciguat-induced vasodilation was significantly less in intrarenal than in mesenteric arteries and not age-dependent. Human intrarenal and mesenteric arteries showed a similar vasodilation in response to SNP and cinaciguat. In both vascular beds arteries with a lumen diameter < 700 μm showed a stronger cinaciguat-induced vasodilation than arteries with a lumen diameter > 700 μm. Cinaciguat (0.1 μmol/l) increased PKG-dependent MYPT1-S668 phosphorylation in <700 μm vessels but not in >700 μm vessels. Cinaciguat significantly reduced MLC-S19 phosphorylation only in <700 μm mesenteric arteries. CONCLUSIONS: In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC-S19 phosphorylation.
Budbazar E, Balmes A, Elliott D
… +6 more, Peres Tintin L, Kopp T, Feil S, Feil R, Schäffer TE, Seta F
Vascul Pharmacol
· 2025 Jun · PMID 40383495
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BACKGROUND & PURPOSE: Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [1] and dementia [2] for which currently there are no targeted therap...BACKGROUND & PURPOSE: Arterial stiffness, or loss of elastic compliance in large arteries, is an independent precursor of cardiovascular disease (CVD) [1] and dementia [2] for which currently there are no targeted therapies. We previously discovered that decreases in NO-sensitive guanylyl cyclase (NO-GC), the NO receptor which synthesizes cGMP, and in its target vasodilator-stimulated phosphoprotein (pVASP), lead to increased cytoskeletal actin polymerization in vascular smooth muscle cells (VSMCs) contributing to increased arterial stiffness [3]. In the current study, we tested whether activating NO-GC with an NO-GC activator (cinaciguat) modulates pVASP and cytoskeletal actin polymerization in VSMCs, thereby preventing obesity-induced arterial stiffness. EXPERIMENTAL APPROACH & KEY RESULTS: Cinaciguat administration (5 mg/kg) to high fat, high sucrose diet (HFHS)-fed mice, our established model of arterial stiffness [4], (1) decreased pulse wave velocity, the in vivo index of arterial stiffness, without affecting blood pressure; (2) increased aortic pVASP levels; and (3) decreased actin polymerization, measured as ratio of filamentous (F) to globular (G) actin, compared to vehicle administration. In cultured VSMCs, cinaciguat (10 μmol/L) increased pVASP levels and decreased the F/G actin ratio at baseline and after stimulation with the cytokine tumor necrosis factor α (TNFα), which we previously showed is significantly increased in the aorta of HFHS-fed mice [4-6]. These effects were abrogated in aortas and VSMCs from mice with smooth muscle-specific cGKI deletion (cGKI), while being mimicked by a cell-permeable cGMP analog (8-Br-cGMP), which also decreased VSMC stiffness in vitro. CONCLUSIONS & IMPLICATIONS: Collectively, our data strongly support the notion that pharmacological NO-GC activation would be beneficial in decreasing obesity-associated arterial stiffness by decreasing VSMC cytoskeletal actin hyper-polymerization. If translated to humans, NO-GC activators could become a viable approach to clinically treat arterial stiffness, which remains an unmet medical need.
Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular diversity in human biology, providing novel insights into disease mechanisms. In cardiovascular disease (CVD), scRNA-seq enables precis...Single-cell RNA sequencing (scRNA-seq) has transformed our understanding of cellular diversity in human biology, providing novel insights into disease mechanisms. In cardiovascular disease (CVD), scRNA-seq enables precise mapping of complex cell populations, uncovering unique cell types and states that influence disease progression and suggest new therapeutic targets. In atherosclerosis (AS), scRNA-seq has redefined plaque pathology by identifying distinct cell types, including endothelial cells (ECs), smooth muscle cells (SMCs), fibroblasts, macrophages, T cells, and B cells, each with specific roles in plaque stability, inflammation, and disease progression. In our review, we summarized these major cellular populations and their cellular heterogeneity in non-diseased and atherosclerotic aorta, as identified by scRNA-seq in mice and human tissues. We discussed conserved and species-specific subpopulations, their defining markers, and their functional implications in plaque progression. In addition, we integrated findings from scRNA-seq with experimental studies to highlight key molecular targets with therapeutic potential. In the future, these insights offer a refined cellular and molecular framework of atherosclerosis and may help the development of targeted interventions to promote plaque stabilization and reduce cardiovascular risk.
BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) improve 30-day outcomes when used as an adjunct to percutaneous coronary intervention (PCI) in acute coronary syndromes, but their role in stable coronary artery diseas...BACKGROUND: Glycoprotein IIb/IIIa inhibitors (GPIs) improve 30-day outcomes when used as an adjunct to percutaneous coronary intervention (PCI) in acute coronary syndromes, but their role in stable coronary artery disease (CAD) remains uncertain in the context of modern stents and oral antiplatelet therapy. METHODOLOGY: A systematic search of PubMed, EMBASE, Central and clinicaltrials.gov databases was conducted from inception to October 2022. Randomised trials comparing GPI to placebo in elective PCI were included. Outcomes included target vessel revascularisation (TVR), stent thrombosis (ST) and a composite of TVR, myocardial infarction and death (MACE) at 30-days and 6-12 months. Bleeding was assessed using Thrombolysis In Myocardial Infarction bleeding score or equivalent. A random-effects model was used for all analyses. RESULTS: Of 2375 abstracts screened, 16 studies (6428 patients) were included. GPIs significantly reduced 30-day MACE (risk ratio [RR] 0.58, 95 % CI, 0.39-0.86, p < 0.01; number needed to treat = 33), intermediate-term MACE at 6-12 months (RR 0.67; 95 % CI, 0.49-0.92; p = 0.01) and ST (RR 0.29, 95 % CI, 0.10-0.83, p = 0.02). There was no significant difference in TVR or major bleeding, although minor bleeding was increased (RR 1.72, 95 % CI, 1.14-2.61, p = 0.01, number needed to harm = 77). Meta-regression suggested that the benefit of GPIs has diminished over time. CONCLUSION: GPI use during elective PCI reduces MACE and ST whilst increasing minor bleeding. The observed benefit appears to have waned over time, highlighting the importance of selective use in patients at low bleeding risk.
Slenders L, Wesseling M, Wei S
… +14 more, Boltjes A, Kapteijn DMC, van de Kraak P, Depuydt MAC, Prange KHM, van den Dungen NAM, Benavente ED, de Kleijn DPV, de Borst GJ, de Winther MPJ, den Ruijter HM, Owens GK, Pasterkamp G, Mokry M
BACKGROUND: Endothelial cells within atherosclerotic plaques can differentiate into a mesenchymal-like phenotype through endothelial-to-mesenchymal transition (EndoMT). Our understanding of the molecular mechanisms under...BACKGROUND: Endothelial cells within atherosclerotic plaques can differentiate into a mesenchymal-like phenotype through endothelial-to-mesenchymal transition (EndoMT). Our understanding of the molecular mechanisms underlying EndoMT in human atherosclerosis remains limited. Current gene expression signatures are often derived from in vitro experiments or animal studies and typically reflect genes upregulated in fully differentiated mesenchymal cell states, while genes upregulated during the process are omitted. To address this knowledge gap, we utilized in silico lineage tracing in single-cell transcriptomic (scRNA-seq) data from human plaque tissues to identify the EndoMT gene expression signature. METHODS AND RESULTS: We constructed three candidate EndoMT lineages across subpopulations of ECs and SMCs in human carotid scRNA-seq data (n = 46). We examined gene expression over the course of these lineages and identified a core signature of 73 genes upregulated in EndoMT. Upregulation of those genes was confirmed in EndoMT trajectories of other human datasets derived from plaque tissue and in Cdh5-Cre Rosa-eYFP apoE lineage-traced mice. Analysis of human carotid plaque bulk RNA-seq data (632 patients) found the association of core gene signature with fibrous and more stable histological phenotypes. CONCLUSION: This study defines the core gene signature of EndoMT in human atherosclerotic plaques, which can serve as a reference for future studies and gene set enrichment analysis.
Aortic stenosis (AS) is a progressive condition characterized by valve calcification and significant morbidity, often requiring invasive intervention. The AS pathophysiology is multifaceted, with evidence suggesting a ro...Aortic stenosis (AS) is a progressive condition characterized by valve calcification and significant morbidity, often requiring invasive intervention. The AS pathophysiology is multifaceted, with evidence suggesting a role for trace elements. However, whether zinc (Zn) and copper (Cu) are associated with valve calcification is unclear. This exploratory study assessed the Zn and Cu levels in the serum and aortic valves of AS patients undergoing surgical valve replacement and explored the relationships between trace elements and clinical and biochemical parameters to better understand their potential roles in AS pathophysiology. An inverse relationship was observed between serum Zn levels and systolic pressure gradients across the valve (p < 0.0001). Zn accumulation was identified in calcified aortic valves, suggesting a systemic redistribution of Zn during disease progression. The valvular Cu/Zn ratio was reversed (<1) compared to that in serum. The lipoprotein(a), an inflammatory marker, was positively correlated with serum Cu levels (p = 0.0007) and the Cu/Zn ratio (p = 0.02). However, no direct association was found between valvular Cu content and the AS severity. The findings suggest that Zn depletion in serum, coupled with its accumulation in calcified valves, reflects a disease-driven redistribution mechanism that may serve a protective role against calcification progression. Additionally, the study highlights a potential interplay between Cu metabolism and inflammatory processes in AS. Further research is required to determine whether therapeutic modulation of Zn levels could offer benefits in AS management.
Gout and hyperuricemia increase cardiovascular disease risk, highlighting the need for improved risk stratification. In this pilot study, we evaluated the Coronary Event Risk Test (CERT) in 94 hyperuricemic and 196 gout...Gout and hyperuricemia increase cardiovascular disease risk, highlighting the need for improved risk stratification. In this pilot study, we evaluated the Coronary Event Risk Test (CERT) in 94 hyperuricemic and 196 gout patients, and 53 controls. Plasma ceramides were determined by liquid chromatography-mass spectrometry. Elevated CERT scores (≥7) occurred in 11.7 % (2-fold increase) of hyperuricemic and 31.12 % (5.5-fold increase) of gout patients compared to controls. Additionally, both hyperuricemic and gout patients with increased CERT also exhibited higher levels of inflammation and atherogenic index of plasma, both of which were significantly associated with CERT. Incorporating CERT into routine care may enhance risk stratification and guide targeted interventions in this patient population.
Atherosclerosis remains a leading cause of morbidity and mortality worldwide, driven by complex molecular mechanisms involving gene regulation and post-transcriptional processes. Emerging evidence highlights the critical...Atherosclerosis remains a leading cause of morbidity and mortality worldwide, driven by complex molecular mechanisms involving gene regulation and post-transcriptional processes. Emerging evidence highlights the critical role of epitranscriptomics, the study of chemical modifications occurring on RNA molecules, in atherosclerosis development. Epitranscriptomics provides a new layer of regulation in vascular health, influencing cellular functions in endothelial cells, smooth muscle cells, and macrophages, thereby shedding light on the pathogenesis of atherosclerosis and presenting new opportunities for novel therapeutic targets. This review provides a comprehensive overview of the epitranscriptomic landscape, focusing on key RNA modifications such as N6-methyladenosine (m6A), 5-methylcytosine (mC), pseudouridine (Ψ), RNA editing mechanisms including A-to-I and C-to-U editing and RNA isoforms. The functional implications of these modifications in RNA stability, alternative splicing, and microRNA biology are discussed, with a focus on their roles in inflammatory signaling, lipid metabolism, and vascular cell adaptation within atherosclerotic plaques. We also highlight how these modifications influence the generation of RNA isoforms, potentially altering cellular phenotypes and contributing to disease progression. Despite the promise of epitranscriptomics, significant challenges remain, including the technical limitations in detecting RNA modifications in complex tissues and the need for deeper mechanistic insights into their causal roles in atherosclerotic pathogenesis. Integrating epitranscriptomics with other omics approaches, such as genomics, proteomics, and metabolomics, holds the potential to provide a more holistic understanding of the disease.
OBJECTIVE: Studies investigating the efficacy of β-blocker agents for patients with thoracic aortic aneurysm (TAA) have produced heterogeneous and conflicting results. We assess the effects of β-blockers on clinical outc...OBJECTIVE: Studies investigating the efficacy of β-blocker agents for patients with thoracic aortic aneurysm (TAA) have produced heterogeneous and conflicting results. We assess the effects of β-blockers on clinical outcomes in patients with TAA. METHODS: A systematic literature search was performed through Ovid MEDLINE, EMBASE, Web of Science, Pubmed and Cochrane CENTRAL, all from inception to April 30, 2024. Randomized controlled trials (RCTs) exploring the effect of β-blocker agents in patients with TAA were considered for inclusion, with no population restriction. Inverse variance-weighted random-effects model was used. The overall risk of bias assessment was conducted by Cochrane Risk of Bias 2 tool. The primary outcome was aortic events during follow-up. RESULTS: We included a total of 161 patients with TAA (mean age, 27.6 years; 80 [49.7 %] male, mean follow-up 6.7 years) in 4 RCTs. The pooled risk ratio in the β-blocker arm for aortic events was 0.74 [95 % CI (0.20; 2.71), I: 0 %, p = 0.64, low certainty of evidence (CoE)] when compared to placebo or no treatment in patients with TAA. The pooled risk ratios for aortic dissection or death (all-cause mortality) or in the β-blocker arm were 0.45 (95 % CI (0.10; 1.98), I: 0 %, p = 0.29, low CoE) and 0.58 (95 % CI (0.15; 2.24), I: 0 %, p = 0.43, low CoE), respectively. The risks of aortic dissection, rupture, or death were comparable, regardless of agent, disease, and age. CONCLUSION: We found no evidence of benefit from β-blocker treatment for patients with TAA. More robust RCTs are needed to establish evidence-based recommendations.
Targeting interleukin-1 beta (IL-1β) to mitigate inflammation is known to stabilize atherosclerotic plaques, thereby lowering the risk of acute cardiovascular events. The precise mechanisms are not yet known. Fideler et...Targeting interleukin-1 beta (IL-1β) to mitigate inflammation is known to stabilize atherosclerotic plaques, thereby lowering the risk of acute cardiovascular events. The precise mechanisms are not yet known. Fideler et al. examined the effects of IL-1β on exaggerated atherosclerosis following clonal hematopoiesis of indeterminate potential (CHIP). Unexpectedly, they showed an effect of IL-1β blockage on fibroblast-like cells and their role in the progression of atherosclerosis in the presence of CHIP. Here, we discuss these findings and place them in context of current insights on plaque fibroblast identity and function. While single cell sequencing studies had observed the presence of plaque fibroblasts in atherosclerotic plaques, their function has yet to be unraveled. By focusing on both in vitro and ex vivo models, the research explored how IL-1β stimulation drives functional and molecular changes in fibroblast-like cells, such as increased cytokine production and enhanced matrix degradation, which replicate the inflammatory microenvironment commonly seen in atherosclerotic lesions. Furthermore, the study suggests that inhibiting IL-1β might encourage the accumulation of fibroblast-like cells within the fibrous cap, a process that could improve plaque stability by reducing inflammatory activity and strengthening the structural integrity of the plaque. Depletion of proteoglycan 4 (Prg4) -positive cells, that represent fibroblasts amongst other cell types, reduced cap thickness in atherosclerosis with clonal hematopoiesis of indeterminate potential. The findings suggest that IL-1β not only plays a critical role in promoting inflammation, but also in altering the phenotype of fibroblast-like cells, contributing to the destabilization of atherosclerotic plaques. This study is the first to show a function of plaque fibroblast-like cells in exaggerated atherosclerosis following clonal hematopoiesis of indeterminate potential. Future studies should confirm this effect in models without clonal hematopoiesis of indeterminate potential, and with fibroblast depletion based on more specific fibroblast genes.
Cerebral small vessel disease (cSVD) is a major cause of vascular cognitive impairment and dementia. The underlying disease mechanisms are centered around the dysfunction of the neurovascular unit and include an impairme...Cerebral small vessel disease (cSVD) is a major cause of vascular cognitive impairment and dementia. The underlying disease mechanisms are centered around the dysfunction of the neurovascular unit and include an impairment of the blood-brain barrier (BBB) permeability, a decreased cerebrovascular reactivity and cerebral hypoperfusion. The cells composing the neurovascular unit express a wide variety of mechanosensitive ion channels that are relevant for these processes. Recent research has increasingly focused on the mechanobiology of cerebral microvessels with recent evidence pointing towards a significant role of transient receptor potential vanilloid 4 (TRPV4). This Ca-permeable channel regulates key physiological functions, including vascular tone, angiogenesis, BBB integrity and neuroinflammation. Beyond its physiological role, recent evidence implicates TRPV4 in pathological processes such as cerebrovascular remodelling, impaired cerebrovascular reactivity, and BBB dysfunction. In this review, we explore the multiple roles of TRPV4 within the neurovascular unit, its interactions with key molecular partners, and we discuss evidence for its potential contribution to cSVD.
Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many...Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many limitations as patients in their final stages of heart failure have little chances of experiencing any reversible changes. In recent decades, Mesenchymal stem cell (MSC) based therapy has become one of the most popular and rapidly developing fields in treating MI. Their supremacy for clinical applications is partially due to their unique properties and encouraging pre-clinical outcomes in various animal disease models. However, the majority of clinical trials registered for MSC therapy for diverse human diseases, including MI, have fallen short of expectations. This review intends to discuss the recent advances in the clinical application of using MSCs for cardiac repair and discuss challenges facing the clinical translation of MSCs for cardiac regeneration such as restoration of endothelial-cardiomyocyte crosstalk, immunomodulation and immune rejection, poor homing and migration, as well as low retention and survival. Furthermore, we will discuss recent strategies being investigated to help overcome some of these challenges.
OBJECTIVE: During growth and differentiation of skeletal muscle, cell types other than canonical myoblasts can be recruited to a myogenic fate. Among these, TNAP+ pericytes can differentiate into skeletal or smooth muscl...OBJECTIVE: During growth and differentiation of skeletal muscle, cell types other than canonical myoblasts can be recruited to a myogenic fate. Among these, TNAP+ pericytes can differentiate into skeletal or smooth muscle cells during postnatal growth and contribute to muscle regeneration. However, their role in muscle development has not been investigated. This study aims to characterise pericyte fate choices during embryonic and foetal myogenesis, occurring in the second half of gestation. APPROACH AND RESULTS: Using Cre-loxP lineage tracing with multiple reporters including the multifluorescent Confetti, we labelled TNAP+ precursors in vivo and assessed the smooth or skeletal muscle differentiation in their lineage at a perinatal stage. We found that TNAP+ cells contribute in vivo to skeletal and smooth muscle cells, as well as other pericytes, also during pre-natal muscle development. The resulting clones showed that such fate choices are likely to depend on distinct unipotent progenitors rather than multipotent progenitors. In addition, we isolated and differentiated in vitro foetal cells derived from TNAP+ precursors, which showed that they are not spontaneously myogenic unless co-cultured with other skeletal muscle cells. CONCLUSIONS: This work extends our understanding of the differentiative potency of these non- canonical skeletal muscle progenitors during prenatal life, with a view to a future application of this knowledge to optimise cell therapies for muscle wasting disorders.
Suur BE, Karadimou G, Willems CJJM
… +11 more, Bergman O, Lengquist M, Kronqvist M, Baumgartner R, Malin S, Gisterå A, Hansson GK, Mälarstig A, Hedin U, Ketelhuth DFJ, Matic L
BACKGROUND: Proprotein convertase subtilisins/kexins (PCSKs) have been implicated in cancers and cardiovascular disease. We have shown that PCSK6 is a key protease regulating smooth muscle cell (SMC)-mediated vascular re...BACKGROUND: Proprotein convertase subtilisins/kexins (PCSKs) have been implicated in cancers and cardiovascular disease. We have shown that PCSK6 is a key protease regulating smooth muscle cell (SMC)-mediated vascular remodeling, but also that it can be expressed by T cells and macrophages in atherosclerotic plaques. Whether PCSK6 regulates innate and adaptive immune responses in the context of vascular inflammation is still unknown. METHODS: In this study, detailed immunophenotyping of constitutive Pcsk6 mice was performed. Bone marrow transplantation into high-cholesterol diet fed Ldlr mice was used to investigate PCSK6-mediated immune effects in atherogenesis and plaque stability. RESULTS: Compared to controls, Pcsk6 mice showed higher plasma levels of the chemoattractants CCL2 and CCCL3, and Th17 cytokines IL-17 A and IL-17F. Pcsk6 ablation led to increased naïve and effector-memory CD4+ and CD8+ cell numbers in the spleen, and increased release of IL-17 A, IFN-γ and IL-10 as well as proliferation by spleenocytes in vitro. Lack of Pcsk6 also affected innate immunity as macrophages from Pcsk6 mice secreted more cytokines, including TNF-α, CCL2, IL-6 and IL-10 upon LPS stimulation in vitro, and were more prone to oxLDL uptake. In line with a pro-inflammatory phenotype, Pcsk6➔Ldlr transplanted mice presented a higher atherosclerotic plaque burden compared to Ldlr receiving control bone marrow. Although larger, Pcsk6➔Ldlr plaques showed increased stability features, including collagen deposition and SMC presence coinciding with significantly increased local levels of the fibrogenic cytokine IL-17. CONCLUSIONS: Global Pcsk6 ablation leads to the activation of both adaptive and innate immune systems. Interestingly, Pcsk6 ablation in bone marrow of hyperlipidemic mice revealed its dual role in atherogenesis, activating a Th17-SMC modulatory axis that promotes plaque stability, despite increased atherosclerotic burden.
BACKGROUND: Cardiovascular diseases remain the leading cause of disability and death in the Western world. Effective cardioprotection involves limiting ischemia/reperfusion injury (IRI), including cell death (pyroptosis)...BACKGROUND: Cardiovascular diseases remain the leading cause of disability and death in the Western world. Effective cardioprotection involves limiting ischemia/reperfusion injury (IRI), including cell death (pyroptosis) driven by the NLRP3 inflammasome. While various cardiac resident cellular populations contribute to cardioprotection, it remains unclear whether targeting resident macrophages is inherently cardioprotective. Given that INF150, an NLRP3 inhibitor, exhibits varying abilities to penetrate cardiomyocytes and macrophages, we sought to address this question. METHODS: We studied the cardioprotective potential of INF150, the potent metabolite of the NLRP3 inhibitor INF195, in isolated hearts or cells. In isolated hearts, we measured infarct size, caspase-1 cleavage, and interleukins (IL) release, while in macrophages, naïve H9c2 and differentiated H9c2 cells, we analyzed cell viability, and pyroptosis markers, including IL-1β release and Gasdermin D cleavage, following hypoxia/reoxygenation (H/R). RESULTS AND CONCLUSION: While INF150 effectively shielded macrophages from LPS/ATP challenges, it failed to penetrate H9c2 and differentiated H9c2, even at high concentrations (no changes in pyroptosis markers induced by H/R). In the isolated mice heart model, INF150 did not demonstrate cardioprotective effects: infarct size, IL-1β, cleaved caspase-1 levels did not change significantly across tested concentrations of INF150. These findings suggest that while INF150 shows promise in macrophage/phagocytic models, its inability to penetrate cardiomyocytes limits its effectiveness in the whole cardiac tissue. Our results underscore the importance of cardiomyocyte uptake for effective cardioprotection, highlighting the need for NLRP3 inhibitors capable of targeting these cells directly. Future research should focus on enhancing the delivery and cardiomyocyte uptake of NLRP3 inhibitors to achieve cardioprotection. Unlike its precursor, INF195, which penetrates H9c2 cells, INF150 does not appear to offer cardioprotection in the whole organ.
Vascular smooth muscle cell (VSMC) contractility mediates blood vessel tone. Abnormalities in VSMC function and in blood vessel tone can contribute to a variety of cardiovascular diseases. This review examines the role o...Vascular smooth muscle cell (VSMC) contractility mediates blood vessel tone. Abnormalities in VSMC function and in blood vessel tone can contribute to a variety of cardiovascular diseases. This review examines the role of VSMC contractile force in vascular disease, divided into two primary sections. The first section introducing VSMC mechanical contraction and detailing the molecular mechanisms of VSMC contractility in normal and pathological states. The second section exploring methods of measuring contraction in VSMCs, such as Ca imaging, myography, and traction force microscopy, and highlighting where each method is of best use. Understanding the mechanical properties and contractile profiles of VSMCs offers valuable insights into disease mechanisms. By investigating these aspects, this review describes the potential of VSMC contractile forces as diagnostic markers and therapeutic targets in vascular disease.
Mitochondria are essential organelles that regulate cellular energy metabolism, redox balance, and signaling pathways related to proliferation, aging and survival. So far, significant interspecies differences exist in mi...Mitochondria are essential organelles that regulate cellular energy metabolism, redox balance, and signaling pathways related to proliferation, aging and survival. So far, significant interspecies differences exist in mitochondrial structure, function, and dynamics, which have critical implications for cardiovascular physiology and pharmacology. This review explores the main differences in mitochondrial properties across species of animals that are commonly used for translational research, emphasizing their cardiac and vascular relevance. By addressing key interspecies differences, including mitochondrial DNA (mtDNA) variation, bioenergetic profile, oxidative stress response, epigenetic regulation, mitochondrial biogenesis, and adaptive mechanisms, we aim to provide insights into the challenges and opportunities in translating preclinical findings to clinical applications. Understanding these interspecies differences is essential for optimizing the design and interpretation of preclinical studies and for developing effective mitochondrial-targeted therapies.