Small artery remodelling in diabetes

The aim of this article is to briefly review available data regarding changes in the structure of microvessels observed in patients with diabetes mellitus, and possible correction by effective treatment. The development of structural changes in the systemic vasculature is the end result of established hypertension. In essential hypertension, small arteries of smooth muscle cells are restructured around a smaller lumen and there is no net growth of the vascular wall, although in some secondary forms of hypertension, a hypertrophic remodelling may be detected. Moreover, in non-insulin-dependent diabetes mellitus a hypertrophic remodelling of subcutaneous small arteries is present. Indices of small resistance artery structure, such as the tunica media to internal lumen ratio, may have a strong prognostic significance in hypertensive and diabetic patients, over and above all other known cardiovascular risk factors. Therefore, regression of vascular alterations is an appealing goal of antihypertensive treatment. Different antihypertensive drugs seem to have different effect on vascular structure. In diabetic hypertensive patients, a significant regression of structural alterations of small resistance arteries with drugs blocking the renin–angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) was demonstrated. Alterations in the microcirculation represent a common pathological finding, and microangiopathy is one of the most important mechanisms involved in the development of organ damage as well as of clinical events in patients with diabetes mellitus. Renin–angiotensin system blockade seems to be effective in preventing/regressing alterations in microvascular structure.     

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT₁) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT₁ receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.     

Bromolasalocid (Ro 20-0006) antihypertensive ionophore

Bromolasalocid (Ro 20-0006) is a calcium ionophore with antihypertensive activity that does not belong to any known class of antihypertensive agents. Bromolasalocid produces a relatively flat systolic blood pressure dose-response effect in the spontaneously hypertensive rat. An intensive cardiovascular evaluation of bromolasalocid at the highest dose used in the dose-response study showed full hemodynamic compensation; there was a significant decrease in both mean arterial blood pressure and peripheral resistance without a significant decrease in cardiac index. The antihypertensive action of bromolasalocid lasts many days after termination of dosing. Bromolasalocid is specifically antihypertensive and does not decrease arterial blood pressure in normotensive animals or in animal models of hypertensive cardiovascular disease with normal pulse pressures. Bromolasalocid is not a vasodilator and appears to mediate its antihypertensive action by restoring compliance of the large conduit arteries. Both the derived arterial compliance index and the blood pressure-pressor response to the carotid occlusion reflex are enhanced in the dog perinephritis model of hypertensive cardiovascular disease treated with bromolasalocid. Bromolasalocid appears to reverse the damage to cardiovascular tissue caused by prolonged hypertension via an action on calcium perturbations in large artery smooth muscle cells.     

Identification of novel proteins and mechanistic pathways associated with early-onset hypertension by deep proteomic mapping of resistance arteries

Resistance arteries are small blood vessels that create resistance to blood flow. In hypertension, resistance arteries undergo remodeling, affecting their ability to contract and relax appropriately. To date, no study has mapped the hypertension-related proteomic changes in resistance arteries. Using a novel data-independent acquisition–mass spectrometry (DIA-MS) approach, we determined the proteomic changes in small mesenteric and renal arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR) model, which represents human primary hypertension. Compared with normotensive controls, mesenteric arteries from 12-week-old SHRs had 286 proteins that were significantly up- or downregulated, whereas 52 proteins were identified as up- or downregulated in mesenteric arteries from 6-week-old SHRs. Of these proteins, 18 were also similarly regulated in SHR renal arteries. Our pathway analyses reveal several novel pathways in the pathogenesis of hypertension. Finally, using a matrisome database, we identified 38 altered extracellular-matrix-associated proteins, many of which have never previously been associated with hypertension. Taken together, this study reveals novel proteins and mechanisms that are associated with early-onset hypertension, thereby providing novel insights into disease progression.     

Vascular smooth muscle polyploidization--from mitotic checkpoints to hypertension

Aging and hypertension are accompanied by an increase in mass and rigidity of arterial walls. At capacitance arteries, the enlargement and stiffness of the medial smooth muscle layer promote systolic hypertension and contribute to left ventricular hypertrophy and cardiovascular morbidity. Morphological studies have demonstrated that vascular smooth muscle cell (VSMC) hypertrophy, with minimal hyperplasia, causes the enlargement of vascular smooth muscle at capacitance arteries, and that VSMC hypertrophy is strongly associated with VSMC polyploidization. Recent studies demonstrate that hypertrophic signals, such as those elicited by Angiotensin II, abrogate the mechanisms of control of M phase in VSMC and induce cell cycle re-entry and polyploidization. These polyploid VSMC have a lower replicative rate, but a higher mass, protein content and matrix production than their diploid counterparts. Both, the protein kinase Aktl and the cyclin kinase-associated protein CKsl, have been implicated in the mechanism of VSMC polyploidization during hypertension. Here, we review the function of these proteins at the mitotic spindle cell cycle checkpoint and their role in the process of VSMC polyploidization.     

A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease

Reactive oxygen species (ROS) are by-products of oxygen metabolism, normally present in low levels inside cells, where they participate in signaling processes. The delicate balance in the continuous cycle of ROS generation and inactivation is maintained by enzymatic and nonenzymatic endogenous systems. Overwhelming production of ROS (by such sources as the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidase, or uncoupled nitric oxide synthase), when inadequately counteracted by destruction through antioxidant systems (such as superoxide dismutase or catalase), leads to a prooxidant state also known as oxidative stress. Increased levels of ROS and markers of oxidative stress have been consistently found in such cardiovascular diseases as atherosclerosis or hypertension, although controversy still exists over the pathophysiological role of oxidative stress in these conditions. ROS can modulate vascular function either by direct oxidative damage or by activating cellular signaling pathways that lead to abnormal contractile, inflammatory, proliferative, or remodeling properties of the blood vessel. Most current research focuses on these processes in arteries, leaving veins, "the other side" of vascular biology, in obscurity. Veins are different structurally and functionally from arteries. Equipped with a smaller smooth muscle layer compared to arteries, but being able to accommodate 70% of the circulating blood volume, veins can modulate cardiovascular homeostasis and contribute significantly to hypertension pathogenesis. Although the reports on the quantitative differences in ROS production in veins compared to arteries had conflicting results, there is a clear qualitative difference in ROS metabolism and utilization between the two vessel types. This review will compare and contrast the current knowledge of ROS metabolism in arteries versus veins in both physiological and pathophysiological conditions. Our understanding of the mechanisms underlying vascular diseases would greatly benefit from a more thorough exploration of the role of veins and venous oxidative stress.     

Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats

Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two‐kidney one‐clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX‐2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.     

Redox signaling in central neural regulation of cardiovascular function

One of the most prominent concepts to emerge in cardiovascular research over the past decade, especially in areas focused on angiotensin II (AngII), is that reactive oxygen species (ROS) are critical signaling molecules in a wide range of cellular processes. Many of the physiological effects of AngII are mediated by ROS, and alterations in AngII-mediated redox mechanisms are implicated in cardiovascular diseases such as hypertension and atherosclerosis. Although most investigations to date have focused on the vasculature as a key player, the nervous system has recently begun to gain attention in this field. Accumulating evidence suggests that ROS have important effects on central neural mechanisms involved in blood pressure regulation, volume homeostasis, and autonomic function, particularly those that involve AngII signaling. Furthermore, oxidant stress in the central nervous system is implicated in the neuro-dysregulation associated with some forms of hypertension and heart failure. The main objective of this review is to discuss the recent progress and prospects for this new field of central redox signaling in cardiovascular regulation, while also addressing the molecular tools that have spurred it forward.     

Speculative approaches in hypertension: concepts and drugs of the future

Despite the availability and application of more effective antihypertensive drugs over the past 3 decades, hypertension continues to be a major risk factor for the development of premature cardiovascular disease. Moreover, failure to elucidate the pathogenesis of essential hypertension, noncompliance, and difficulties in defining the appropriate level of blood pressure elevation requiring therapy, continue to mitigate against the adequate control of hypertension. Some of these problems may be overcome by the availability of depot forms of antihypertensive medication or implantable drug delivery systems, or by the use of several recently developed antihypertensive drugs. These include dopaminergic agonists, selective alpha-adrenergic agents, calcium antagonists, medullary neutral lipids, gamma-aminobutyric acid agonists, and inhibitors of renin or phenethylamine N-methyl-transferase. In addition, the potential involvement of morphinomimetic peptides, prostaglandins, tonin, and bradykinin in blood pressure control or certain hypertensive states suggests that drugs developed to block or potentiate the actions of these substances may have important therapeutic applications.     

Effect of antihypertensive treatment on small artery remodeling in hypertension

Blood vessels are remodeled in hypertension both structurally and functionally. The changes that occur in their structure, mechanical properties, and function contribute to blood pressure elevation and to complications of hypertension. We studied the remodeling of small arteries in experimental animals and humans. Smooth muscle cells of small arteries are restructured around a smaller lumen, with significant remodeling of the extracellular matrix and collagen and fibronectin deposition. Interestingly, there is no evidence of net growth of the vascular wall (which results in so-called eutrophic remodeling), particularly in the milder forms of human essential hypertension. Hypertrophic remodeling and increased small artery stiffness may be found in more severe forms of hypertension. Almost all hypertensive patients have vascular structural remodeling. However, only some exhibit endothelial dysfunction. This is particularly true in mild hypertension, in which endothelial dysfunction is less common. A 1-year treatment of hypertensive patients with angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long acting calcium channel blockers corrected small artery structure and, to variable degrees depending on the agents used, impaired endothelial function. In contrast, beta blockers did not improve structure, function, or mechanics of vessels. When beta-blocker-treated patients were switched to an AT1 receptor antagonist, small artery structure and impaired endothelial function were corrected. The vascular protective action of some antihypertensive agents may contribute to improve outcome for hypertensive patients, although this is presently unproven.     

Deficit of glucocorticoid-induced leucine zipper amplifies angiotensin-induced cardiomyocyte hypertrophy and diastolic dysfunction

Poor prognosis in heart failure and the lack of real breakthrough strategies validate targeting myocardial remodelling and the intracellular signalling involved in this process. So far, there are no effective strategies to counteract hypertrophy, an independent predictor of heart failure progression and death. Glucocorticoid-induced leucine zipper (GILZ) is involved in inflammatory signalling, but its role in cardiac biology is unknown. Using GILZ-knockout (KO) mice and an experimental model of hypertrophy and diastolic dysfunction, we addressed the role of GILZ in adverse myocardial remodelling. Infusion of angiotensin II (Ang II) resulted in myocardial dysfunction, inflammation, apoptosis, fibrosis, capillary rarefaction and hypertrophy. Interestingly, GILZ-KO showed more evident diastolic dysfunction and aggravated hypertrophic response compared with WT after Ang II administration. Both cardiomyocyte and left ventricular hypertrophy were more pronounced in GILZ-KO mice. On the other hand, Ang II–induced inflammatory and fibrotic phenomena, cell death and reduction in microvascular density, remained invariant between the WT and KO groups. The analysis of regulators of hypertrophic response, GATA4 and FoxP3, demonstrated an up-regulation in WT mice infused with Ang II; conversely, such an increase did not occur in GILZ-KO hearts. These data on myocardial response to Ang II in mice lacking GILZ indicate that this protein is a new element that can be mechanistically involved in cardiovascular pathology.     

Revisiting PPARγ as a target for the treatment of metabolic disorders

As the prevalence of obesity has increased explosively over the last several decades, associated metabolic disorders, including type 2 diabetes, dyslipidemia, hypertension, and cardiovascular diseases, have been also increased. Thus, new strategies for preventing and treating them are needed. The nuclear peroxisome proliferator-activated receptors (PPARs) are involved fundamentally in regulating energy homeostasis; thus, they have been considered attractive drug targets for addressing metabolic disorders. Among the PPARs, PPARγ is a master regulator of gene expression for metabolism, inflammation, and other pathways in many cell types, especially adipocytes. It is a physiological receptor of the potent anti-diabetic drugs of the thiazolidinediones (TZDs) class, including rosiglitazone (Avandia). However, TZDs have undesirable and severe side effects, such as weight gain, fluid retention, and cardiovascular dysfunction. Recently, many reports have suggested that PPARγ could be modulated by post-translational modifications (PTMs), and modulation of PTM has been considered as novel approaches for treating metabolic disorders with fewer side effects than the TZDs. In this review, we discuss how PTM of PPARγ may be regulated and issues to be considered in making novel anti-diabetic drugs that can modulate the PTM of PPARγ. [BMB Reports 2014; 47(11): 599-608]     

Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway

The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor β-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.     

Application of plasma lipidomics in studying the response of patients with essential hypertension to antihypertensive drug therapy

Hypertension is a key risk factor in the progression of cardiovascular disease (CVD). Dyslipidemia, a strong predictor of CVD, frequently coexists with hypertension. Therefore, the control of hypertension and dyslipidemia may help reduce CVD morbidity and mortality. In the present study, the therapeutic effects of antihypertensive agents on blood pressure control and plasma lipid metabolism were evaluated. The plasma lipid profiles of patients with treated (n = 25) or untreated (n = 30) essential hypertension as well as of subjects with normotension (n = 28) were analyzed using liquid chromatography mass spectrometry. Principal component analysis of the lipidomics data revealed distinct clusters among studied subjects across three human populations. Phosphatidylcholines and triacylglycerols (TG) dominated the pattern of hypertension-influenced plasma lipid metabolism. Discriminatory lipid metabolites were analyzed using one-way analysis of variance followed by a post hoc multiple comparison correction. TG lipid class was significantly increased by 49.0% (p < 0.001) in hypertensive vs. normotensive groups while tended to decrease (-21.2%, p = 0.054) in hypertensive patients after treatment. Total cholesteryl esters were significantly decreased by -16.9% (p < 0.001) in hypertensive patients after treatment. In particular, a large number of individual neutral lipid species were significantly elevated in hypertensive subjects but significantly decreased after treatment with antihypertensive agents. The present study applied, for the first time, a systems biology based lipidomics approach to investigate differentiation among plasma lipid metabolism of patients with treated/untreated essential hypertension and subjects with normotension. Our results demonstrate that antihypertensive medications to lower blood pressure of hypertensive patients to target levels produced moderate plasma lipid metabolism improvement of patients with hypertension.     

Comparing six antihypertensive medication classes for preventing new‐onset diabetes mellitus among hypertensive patients: a network meta‐analysis

Hypertensive patients usually have a higher risk of new‐onset diabetes mellitus (NOD) which may trigger cardiovascular diseases. In this study, the effectiveness of six antihypertensive agents with respect to NOD prevention in hypertensive patients was assessed. A network meta‐analysis was conducted to compare the efficacy of specific drug classes. PubMed and Embase databases were searched for relevant articles. Results of the pairwised meta‐analysis were illustrated by odd ratios (OR) and a corresponding 95% confidence interval (CI). The probabilities and outcome of each treatment were ranked and summarized using the surface under the cumulative ranking curve (SUCRA).Twenty‐three trials were identified, including 224,832 patients with an average follow‐up period of 3.9 ± 1.0 years. The network meta‐analysis showed that patients treated by angiotensin II receptor blockers (ARBs) were associated with a lower risk of NOD compared to placebo (PCB), calcium channel blockers (CCBs) and β‐blockers, while diuretic appeared to be ineffective for NOD prevention. Network meta‐analysis results of specific drugs showed that enalapril exhibited distinct advantages and hydrochlorothiazide also exhibited a reliable performance. Our results suggested that both ARBs and angiotensin converse enzyme inhibitors (ACEIs), especially candesartan and enalapril, were preferable for NOD prevention in hypertensive patients. Hydrochlorothiazide also exhibited a reliable performance in comparison with other agents.     

Rostafuroxin: an ouabain antagonist that corrects renal and vascular Na+-K+- ATPase alterations in ouabain and adducin-dependent hypertension

The genetic and environmental heterogeneity of essential hypertension is responsible for the individual variability of antihypertensive therapy. An understanding of the molecular mechanisms underlying hypertension and related organ complications is a key aspect for developing new, effective, and safe antihypertensive agents able to cure the cause of the disease. Two mechanisms, among others, are involved in determining the abnormalities of tubular Na+ reabsorption observed in essential hypertension: the polymorphism of the cytoskeletal protein alpha-adducin and the increased circulating levels of endogenous ouabain (EO). Both lead to increased activity and expression of the renal Na+-K+ pump, the driving force for tubular Na transport. Morphological and functional vascular alterations have also been associated with EO. Rostafuroxin (PST 2238) is a new oral antihypertensive agent able to selectively antagonize EO, adducin pressor, and molecular effects. It is endowed with high potency and efficacy in reducing blood pressure and preventing organ hypertrophy in animal models representative of both adducin and EO mechanisms. At molecular level, in the kidney, Rostafuroxin antagonizes EO triggering of the Src-epidermal growth factor receptor (EGFr)-dependent signaling pathway leading to renal Na+-K+ pump, and ERK tyrosine phosphorylation and activation. In the vasculature, it normalizes the increased myogenic tone caused by nanomolar ouabain. A very high safety ratio and an absence of interaction with other mechanisms involved in blood pressure regulation, together with initial evidence of high tolerability and efficacy in hypertensive patients, indicate Rostafuroxin as the first example of a new class of antihypertensive agents designed to antagonize adducin and EO-hypertensive mechanisms.     

Kefir ameliorates hypertension via gut–brain mechanisms in spontaneously hypertensive rats

Hypertension is associated with gut dysbiosis and dysregulation of the gut–brain axis. Previous work has shown that probiotic treatments exert beneficial cardiovascular effects in humans and animal models of hypertension. Coupled with the evidence of elevated sympathetic outflow and chronic inflammation in hypertension, we hypothesized that both peripherally and centrally mediated mechanisms underlie the antihypertensive effects of kefir, a probiotic obtained from the fermentation of milk by kefir grains. Eight-week-old spontaneously hypertensive rats (SHRs) were treated by oral gavage with either vehicle or kefir (0.3 ml/100 g/day; 9 weeks; SHR-Kefir), and age-matched with vehicle-treated Wistar Kyoto rats (WKY). Long-term kefir treatment attenuated mean arterial pressure elevations in SHR-Kefir relative to vehicle-treated SHRs. Peripherally, SHRs exhibited differences in the wall of the jejunum (fewer Paneth cells per crypt of Lieberkϋhn and increased tunica muscularis thickness) and higher serum lipopolysaccharide levels compared to WKY, alterations which were reversed in SHR-Kefir. Centrally, kefir treatment reduced IL-6 and TNF-α protein densities, and abolished the microglial activation observed in the hypothalamic paraventricular nucleus and rostral ventrolateral medulla of SHRs. Taken together, our findings indicate that the antihypertensive effects of long-term kefir treatment occur, at least in part, through improved structural and functional integrity of the intestinal wall and protection against neuroinflammation within cardioregulatory nuclei.     

Mineralocorticoid receptors in immune cells: Emerging role in cardiovascular disease

Mineralocorticoid receptors (MRs) contribute to the pathophysiology of hypertension and cardiovascular disease in humans. As such, MR antagonists improve cardiovascular outcomes but the molecular mechanisms remain unclear. The actions of the MR in the kidney to increase blood pressure are well known, but the recent identification of MRs in immune cells has led to novel discoveries in the pathogenesis of cardiovascular disease that are reviewed here. MR regulates macrophage activation to the pro-inflammatory M1 phenotype and this process contributes to the pathogenesis of cardiovascular fibrosis in response to hypertension and to outcomes in mouse models of stroke. T lymphocytes have recently been implicated in the development of hypertension and cardiovascular fibrosis in mouse models. MR activation in vivo promotes T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets while decreasing the number of anti-inflammatory T regulatory lymphocytes. The mechanism likely involves activation of MR in antigen presenting dendritic cells that subsequently regulate Th1/Th17 polarization by production of cytokines. Alteration of the balance between T helper and T regulatory lymphocytes contributes to the pathogenesis of hypertension and atherosclerosis and the associated complications. B lymphocytes also express the MR and specific B lymphocyte-derived antibodies modulate the progression of atherosclerosis. However, the role of MR in B lymphocyte function remains to be explored. Overall, recent studies of MR in immune cells have identified new mechanisms by which MR activation may contribute to the pathogenesis of organ damage in patients with cardiovascular risk factors. Conversely, inhibition of leukocyte MR may contribute to the protective effects of MR antagonist drugs in cardiovascular patients. Further understanding of the role of MR in leukocyte function could yield novel drug targets for cardiovascular disease.