Search Results (265)

The pivotal role of angiotensin II (AngII) in cardiovascular disease has been firmly established, as evidenced by a robust body of literature and the broad clinical application of AngII-inhibiting therapies. AngII type 1 receptor is the primary mediator of AngII action, and its activation initiates a multitude of cellular responses that contribute to the development of hypertension, structural changes in the heart and vasculature, and damage to target organs. This review examines AngII from a different perspective, exploring the link between the renin–angiotensin–aldosterone system and cardiovascular risk beyond hypertension, with particular emphasis on atherosclerosis development and progression. Full article

Primary aldosteronism (PA), the most common cause of secondary hypertension, is increasingly recognized as an independent driver of adverse cardiac remodeling, mediated through mechanisms beyond elevated blood pressure alone. Chronic aldosterone excess leads to myocardial fibrosis, left ventricular hypertrophy, and diastolic dysfunction via mineralocorticoid receptor activation, oxidative stress, inflammation, and extracellular matrix dysregulation. These changes culminate in a distinct cardiomyopathy phenotype, often underrecognized in early stages. Multimodality cardiac imaging, led primarily by conventional and speckle-tracking echocardiography, and complemented by exploratory cardiac magnetic resonance (CMR) techniques such as T1 mapping and late gadolinium enhancement, enables non-invasive assessment of structural, functional, and tissue-level changes in aldosterone-mediated myocardial damage. While numerous studies have established the diagnostic and prognostic relevance of imaging in PA, several gaps remain. Specifically, the relative sensitivity of different modalities in detecting subclinical myocardial changes, the long-term prognostic significance of imaging biomarkers, and the differential impact of adrenalectomy versus medical therapy on cardiac reverse remodeling require further clarification. Moreover, the lack of standardized imaging-based criteria for defining and monitoring PA-related cardiomyopathy hinders widespread clinical implementation. This narrative review aims to synthesize current knowledge on the pathophysiological mechanisms of aldosterone-induced cardiac remodeling, delineate the strengths and limitations of existing imaging modalities, and critically evaluate the comparative effects of surgical and pharmacologic interventions. Emphasis is placed on early detection strategies, identification of imaging biomarkers with prognostic utility, and integration of multimodal imaging into clinical decision-making pathways. By outlining current evidence and highlighting key unmet needs, this review provides a framework for future research aimed at advancing personalized care and improving cardiovascular outcomes in patients with PA. Full article

The mineralocorticoid receptor (MR), traditionally associated with renal function, has also been identified in various extrarenal tissues, including the heart, brain, and dorsal root ganglion (DRG) neurons in rodents. Previous studies suggest a role for the MR in modulating peripheral nociception, with MR activation in rat DRG neurons by its endogenous ligand, aldosterone. This study aimed to determine whether MR, its protective enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), its endogenous ligand aldosterone, and the aldosterone-synthesizing enzyme CYP11B2 are expressed in human DRG neurons and whether they colocalize with key pain-associated signaling molecules as potential targets for genomic regulation. To this end, we performed mRNA transcript profiling and immunofluorescence confocal microscopy on human and rat DRG tissues. We detected mRNA transcripts for MR, 11β-HSD2, and CYP11B2 in human DRG, alongside transcripts for key thermosensitive and nociceptive markers such as TRPV1, the TTX-resistant sodium channel Nav1.8, and the neuropeptides CGRP and substance P (Tac1). Immunofluorescence analysis revealed substantial colocalization of MR with 11β-HSD2 and CGRP, a marker of unmyelinated C-fibers and thinly myelinated Aδ-fibers, in human DRG. MR immunoreactivity was primarily restricted to small- and medium-diameter neurons, with lower expression in large neurons (>70 µm). Similarly, aldosterone colocalized with CYP11B2 and MR with nociceptive markers including TRPV1, Nav1.8, and TrkA in human DRG. Importantly, functional studies demonstrated that prolonged intrathecal inhibition of aldosterone synthesis within rat DRG neurons, using an aldosterone synthase inhibitor significantly downregulated pain-associated molecules and led to sustained attenuation of inflammation-induced hyperalgesia. Together, these findings identify a conserved peripheral MR signaling axis in humans and highlight its potential as a novel target for pain modulation therapies. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is one of the fastest-growing hepatic disorders worldwide. During its natural course, MASLD tends to progress from isolated steatosis of the liver to Metabolic Dysfunction-Associated Alcoholic Steatohepatitis (MASH), advanced fibrosis, and finally cirrhosis, with the risk of developing hepatocellular carcinoma (HCC). Although frequently related to overweight or obesity and other components of the metabolic syndrome (MS), MASLD can also be present in individuals without such risk factors. The mechanisms leading to MASLD are incompletely elucidated and may involve many proinflammatory and pro-fibrotic pathways, disrupted biliary acid homeostasis, and gut microbiota dysbiosis. Aldosterone and its interaction with the mineralocorticoid receptor (MR) are thought to participate in the pathogenesis of MASLD through the modulation of inflammation and fibrosis. Remarkably, blockade of the MR in experimental models was shown to improve MASH and fibrosis through mechanisms that need further characterization. So far, however, few clinical studies have explored the effect of MR blockade in the management of MASH and associated fibrosis. This review is intended to summarize the recent animal and human data concerning the interaction between MR pathways and MASLD. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Acute heart failure (AHF) is a clinical syndrome characterized by the sudden onset or rapid worsening of heart failure signs and symptoms, frequently triggered by myocardial ischemia, pressure overload, or cardiotoxic injury. A central component of its pathophysiology is the activation of intracellular signal transduction cascades that translate extracellular stress into cellular responses. Among these, the mitogen-activated protein kinase (MAPK) pathways have received considerable attention due to their roles in mediating inflammation, apoptosis, hypertrophy, and adverse cardiac remodeling. The canonical MAPK cascades—including extracellular signal-regulated kinases (ERK1/2), p38 MAPK, and c-Jun N-terminal kinases (JNK)—are activated by upstream stimuli such as angiotensin II (Ang II), aldosterone, endothelin-1 (ET-1), and sustained catecholamine release. Additionally, emerging evidence highlights the role of receptor-mediated signaling, cellular stress, and myeloid cell-driven coagulation events in linking MAPK activation to fibrotic remodeling following myocardial infarction. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascade plays a central role in regulating cardiomyocyte survival, hypertrophy, energy metabolism, and inflammation. Activation of the PI3K/Akt pathway has been shown to confer cardioprotective effects by enhancing anti-apoptotic and pro-survival signaling; however, aberrant or sustained activation may contribute to maladaptive remodeling and progressive cardiac dysfunction. In the context of AHF, understanding the dual role of this pathway is crucial, as it functions both as a marker of compensatory adaptation and as a potential therapeutic target. Recent reviews and preclinical studies have linked PI3K/Akt activation with reduced myocardial apoptosis and attenuation of pro-inflammatory cascades that exacerbate heart failure. Among the multiple signaling pathways involved, glycogen synthase kinase-3β (GSK-3β) has emerged as a key regulator of apoptosis, inflammation, metabolic homeostasis, and cardiac remodeling. Recent studies underscore its dual function as both a negative regulator of pathological hypertrophy and a modulator of cell survival, making it a compelling therapeutic candidate in acute cardiac settings. While earlier investigations focused primarily on chronic heart failure and long-term remodeling, growing evidence now supports a critical role for GSK-3β dysregulation in acute myocardial stress and injury. This comprehensive review discusses recent advances in our understanding of the MAPK signaling pathway, the PI3K/Akt cascade, and GSK-3β activity in AHF, with a particular emphasis on mechanistic insights, preclinical models, and emerging therapeutic targets. Full article

The renin-angiotensin-aldosterone system (RAAS) is a hormone system that controls blood pressure and fluid and electrolyte balance. Angiotensin II, a key effector, is produced from angiotensin I by angiotensin-converting enzyme (ACE) and exerts its effects through binding to its type 1 (AT1R) or type 2 (AT2R) receptors. AT1R activation promotes vasoconstriction, oxidative stress, endothelial dysfunction, peripheral vascular resistance, and atherosclerosis, all of which substantially contribute to cellular senescence and organismal ageing. Conversely, AT2R activation counteracts these effects by inducing vascular relaxation and attenuating vascular cell proliferation and migration, offering protection against occlusive vascular disease. Additionally, conversion of angiotensin II to angiotensin (1-7) or angiotensin I to angiotensin (1-9) by ACE2 provides further cardiovascular protection by lowering oxidative stress, inflammation, and abnormal cell growth. Bearing these in mind, measures to control angiotensin II synthesis or receptor activity have been at the forefront of antihypertensive treatment. This paper briefly reviews the RAAS and explores the dual role of angiotensin II in promoting disease and mediating vascular protection, with a focus on its impact on ageing and cardiovascular pathology. Full article

Background: Primary aldosteronism is characterized by elevated aldosterone levels, leading to adverse effects such as hypertension, hypokalaemia and increased risk for cardiovascular and cerebrovascular events. Aldosterone impacts the central nervous system by promoting vascular remodelling and oxidative stress, potentially impairing cognitive function. The presence of mineralocorticoid receptors in the hippocampus, a key region for cognition, further suggest a link between primary aldosteronism and cognitive dysfunction. This study aims to further explore the association between hyperaldosteronism and cognitive impairment. Methods: In this pilot study we examined 15 individuals with primary aldosteronism and arterial hypertension alongside 15 age- and sex-matched controls with essential hypertension, all free of previous cerebrovascular events. Clinical and archival laboratory data were obtained. Cognitive function was assessed using the Mini-Mental State Examination and Montreal Cognitive Assessment. Results: Participants with primary aldosteronism had higher blood pressure values, longer duration of hypertension, lower serum potassium levels and higher 24 h urine albumin excretion rate compared to controls. Comorbidities, other characteristics and laboratory values were comparable across the two groups. No differences were observed in Mini-Mental State Examination scores, but Montreal Cognitive Assessment scores were significantly lower in the primary aldosteronism group (25.1 ± 2.2 vs. 27.1 ± 2.2, p = 0.021). Trends of poorer performance in language and attention/executive function domains were noted in primary aldosteronism individuals, as well as a higher number of pathological Montreal Cognitive Assessment scores (7 vs. 3). No significant correlations were found between cognitive test results and aldosterone concentrations or blood pressure in primary aldosteronism group. However, importantly, multiple regression analysis showed that aldosterone levels have a significant impact on Montreal Cognitive Assessment test, independent of blood pressure or duration of hypertension. Conclusions: This study supports an association between hyperaldosteronism and cognitive dysfunction, underscoring the need for more active detection and targeted treatment of primary aldosteronism. These findings warrant further research in larger cohorts to better elucidate this relationship. Full article

Background/Objectives: Pseudohypoaldosteronism type 1 (PHA-1) is a rare disorder characterized by aldosterone resistance, leading to hyponatremia, hyperkalemia, and elevated renin and aldosterone levels in neonates and infants. While genetic mutations in NR3C2 (mineralocorticoid receptor, MR) and SCNN1A/B/G (epithelial sodium channel, ENaC) are established causes of primary PHA-1, cases without detectable mutations have also been reported. This study aimed to compare the clinical characteristics of genetically confirmed PHA-1 cases—with or without mutations—and to assess genotype–phenotype correlations. Methods: A literature review was conducted using the Medline database, covering studies published from 1966 to October 2023. Included cases were diagnosed with PHA-1 and had undergone genetic testing for NR3C2 and SCNN1A/B/G. Clinical and biochemical data were compared across three groups: MR, ENaC, and non-mutation. Additional subgroup analysis based on mutation type (truncating vs. non-truncating) was also performed. Results: A total of 164 patients from 64 studies met the inclusion criteria. The ENaC group showed significantly higher serum potassium levels than the MR and non-mutation groups. Serum aldosterone levels were significantly higher in the MR group compared to the non-mutation group. A genotype–phenotype correlation was evident in the ENaC group, with truncating variants associated with more severe hyperkalemia. No such correlation was observed in the MR group. Conclusions: This review highlights distinct clinical features of PHA-1 according to genetic status. Aldosterone levels may aid in guiding decisions regarding genetic testing. Furthermore, variant type in ENaC-related PHA-1 may predict biochemical severity and should be considered in clinical management strategies. Full article

Aldosterone, a mineralocorticoid hormone synthesised in the adrenal cortex, is essential for maintaining electrolyte balance and fluid homeostasis. Its role in feline physiology remains underexplored, despite its importance in regulating sodium reabsorption and potassium excretion via mineralocorticoid receptors in renal tubules. This study is warranted given aldosterone’s importance in cats, particularly in light of their unique physiological traits, including highly concentrated urine and sensitivity to hydration status. Primary hyperaldosteronism, the most common feline adrenocortical disorder, contributes to arterial hypertension and chronic kidney disease, yet often remains underdiagnosed due to overlapping symptoms like hypokalaemia and hypertension. This research aimed to validate a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method to measure serum aldosterone and to establish a reference interval in a population of healthy cats across a broad age range. The method demonstrated high precision and accuracy, with inter-assay coefficients of variation under 15%. Analysis of 49 healthy cats (40 young, 9 old) revealed a reference interval of 5.0–78.4 pg/mL (13.8–217.2 pmol/L). These findings provide a robust framework for diagnosing aldosterone-related disorders in cats and underscore the need for species-specific diagnostic tools. Improved understanding of aldosterone’s role could refine treatment strategies and enhance outcomes for affected feline patients. Full article

Background/Objectives: Current guidelines for the management of type 2 diabetes (T2D) strongly recommend the use of sodium–glucose cotransporter 2 inhibitors (SGLT2is) in patients with chronic kidney disease (CKD) to alleviate cardiorenal risk. However, the implementation of this guidance in daily practice remains limited. In a real-world setting, we evaluated the frequency of SGLT2i use in elderly people with T2D and CKD and compared patient profiles between SGLT2i users and non-users. Methods: We retrospectively analyzed the medical records of individuals over 65 years of age followed in outpatient internal medicine clinics in Greece. Demographic and laboratory parameters, comorbidity profiles, and medication use were recorded and compared between the SGLT2i and non-SGLT2i groups. Results: The analysis included 135 patients with T2D and CKD, of whom the majority (57.8%) did not receive SGLT2i treatment. The patients in the SGLT2i group were younger (p = 0.006), had higher creatinine (p = 0.001) and hemoglobin (p = 0.001) values, and lower levels of uric acid (p = 0.025) than the participants not treated with SGLT2is. Heart failure rates were similar between the groups (p = 0.252). There was no difference in the use of renin–angiotensin–aldosterone system inhibitors (p = 0.210); in contrast, treatment with glucagon-like peptide 1 receptor agonists was more frequent in the group receiving SGLT2is compared to the group not treated with gliflozins (p = 0.002). Conclusions: Real-world data confirm the benefits of SGLT2i treatment for elderly people with T2D and CKD. However, our findings indicate that the use of gliflozins in this population of patients remains suboptimal, highlighting the need for greater vigilance among prescribers to align with existing guidelines. Full article

Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD) and is a risk factor for progression to end-stage kidney disease and cardiovascular morbidity and mortality. Despite pharmacologic treatment, residual risk of disease progression and adverse outcomes remains substantial. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist (MRA) approved in the United States for use in patients with CKD associated with T2D. The present review focuses on finerenone use, including its pharmacologic basis, indication and eligibility, and practical aspects of incorporation into routine clinical practice (particularly primary care). Results from the two placebo-controlled phase 3 clinical trials of finerenone (plus maximum tolerated dose of a renin-angiotensin-aldosterone system inhibitor) in patients with CKD associated with T2D showed a significantly lower risk of CKD progression and cardiovascular events with finerenone versus placebo. These effects of finerenone were applicable across the broad spectrum of patient participants, including those with baseline comorbidities such as a history of heart failure or a history of atherosclerotic cardiovascular disease. We also compare finerenone to steroidal MRAs and discuss the relevance of ongoing and recently completed clinical trials of finerenone in other patient groups, which could expand finerenone use further to a broader spectrum of patients. Full article

Pituitary cells are specialized cells located within the pituitary gland, a small, pea-sized gland situated at the base of the brain. Through the use of cellular electrophysiological techniques, the electrical properties of these cells have been revealed. This review paper aims to introduce the ion currents that are known to be functionally expressed in pituitary cells. These currents include a voltage-gated Na⁺ current (I_Na), erg-mediated K⁺ current (I_K(erg)), M-type K⁺ current (I_K(M)), hyperpolarization-activated cation current (I_h), and large-conductance Ca²⁺-activated K⁺ (BK_Ca) channel. The biophysical characteristics of the respective ion current were described. Additionally, we also provide explanations for the effect of various drugs or compounds on each of these currents. GH₃-cell exposure to GV-58 can increase the magnitude of I_Na with a concurrent rise in the inactivation time constant of the current. The presence of esaxerenone, an antagonist of the aldosterone receptor, directly suppresses the magnitude of peak and late I_Na. Risperidone, an atypical antipsychotic agent, is effective at suppressing the I_K(erg) amplitude directly, and di(2-ethylhexyl)-phthalate suppressed I_K(erg). Solifenacin and kynurenic acid can interact with the K_M channel to stimulate I_K(M), while carisbamate and cannabidiol inhibit the I_h amplitude activated by sustained hyperpolarization. Moreover, the presence of either rufinamide or QO-40 can enhance the activity of single BK_Ca channels. To summarize, alterations in ion currents within native pituitary cells or pituitary tumor cells can influence their functional activity, particularly in processes like stimulus–secretion coupling. The effects of small-molecule modulators, as demonstrated here, bear significance in clinical, therapeutic, and toxicological contexts. Full article

Hypertension-induced cardiac remodeling is a complex process driven by interconnected molecular and cellular mechanisms that culminate in hypertensive myocardium, characterized by ventricular hypertrophy, fibrosis, impaired angiogenesis, and myocardial dysfunction. This review discusses the histomorphometric changes in capillary density, fibrosis, and mast cells in the hypertensive myocardium and delves into the roles of key regulatory systems, including the apelinergic system, vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathways, and nitric oxide (NO)/nitric oxide synthase (NOS) signaling in the pathogenesis of hypertensive heart disease (HHD). Capillary rarefaction, a hallmark of HHD, contributes to myocardial ischemia and fibrosis, underscoring the importance of maintaining vascular integrity. Targeting capillary density (CD) through antihypertensive therapy or angiogenic interventions could significantly improve cardiac outcomes. Myocardial fibrosis, mediated by excessive collagen deposition and influenced by fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta (TGF-β), plays a pivotal role in the structural remodeling of hypertensive myocardium. While renin–angiotensin–aldosterone system (RAAS) inhibitors show anti-fibrotic effects, more targeted therapies are needed to address fibrosis directly. Mast cells, though less studied in humans, emerge as critical regulators of cardiac remodeling through their release of pro-fibrotic mediators such as histamine, tryptase, and FGF-2. The apelinergic system emerges as a promising therapeutic target due to its vasodilatory, anti-fibrotic, and cardioprotective properties. The system counteracts the deleterious effects of the RAAS and has demonstrated efficacy in preclinical models of hypertension-induced cardiac damage. Despite its potential, human studies on apelin analogs remain limited, warranting further exploration to evaluate their clinical utility. VEGF signaling plays a dual role, facilitating angiogenesis and compensatory remodeling during the early stages of arterial hypertension (AH) but contributing to maladaptive changes when dysregulated. Modulating VEGF signaling through exercise or pharmacological interventions has shown promise in improving CD and mitigating hypertensive cardiac damage. However, VEGF inhibitors, commonly used in oncology, can exacerbate AH and endothelial dysfunction, highlighting the need for therapeutic caution. The NO/NOS pathway is essential for vascular homeostasis and the prevention of oxidative stress. Dysregulation of this pathway, particularly endothelial NOS (eNOS) uncoupling and inducible NOS (iNOS) overexpression, leads to endothelial dysfunction and nitrosative stress in hypertensive myocardium. Strategies to restore NO bioavailability, such as tetrahydrobiopterin (BH₄) supplementation and antioxidants, hold potential for therapeutic application but require further validation. Future studies should adopt a multidisciplinary approach to integrate molecular insights with clinical applications, paving the way for more personalized and effective treatments for HHD. Addressing these challenges will not only enhance the understanding of hypertensive myocardium but also improve patient outcomes and quality of life. Full article

Smoltification is stressful for salmonids, and cortisol is one of the central endocrine regulators for seawater adaptation. It has been established that cortisol plays both mineralocorticoid and glucocorticoid functions by MR and GR, respectively, since the aldosterone hormone is absent. Recently, investigations have proposed that the 11-deoxycorticosterone (DOC) mineralocorticoid precursor might support cortisol effects, but this mechanism remains unclear. Hence, we assessed the early effects of DOC on rainbow trout pre-smolts, the key smoltification stage, via metabolic and transcriptomic approaches. Thirty-six juveniles (~120 g) were treated for 3 h with DOC (1 mg/kg) and/or mineralocorticoid (eplerenone) or glucocorticoid (mifepristone) receptor antagonists (n = 6 for each group). DOC decreased plasma glucose and pyruvate and increased phosphate and liver glycogen. DOC also downregulated carbohydrate metabolism-related genes in the liver. Finally, gill RNA-seq analysis presented 1660 differentially expressed transcripts in DOC versus vehicle, 1022 for eplerenone + DOC versus DOC and 3324 for mifepristone + DOC versus DOC. The enrichment analysis mainly revealed the upregulation of ion transmembrane transport and carbohydrate metabolism and the downregulation of stress and innate immune responses. This suggests a significant role of DOC in liver carbohydrate metabolism and gill osmoregulation of pre-smolts through both receptors. Hence, this could contribute to improving animal welfare monitoring during smoltification by featuring novel and potential biomarkers. Full article