Mineralocorticoid receptor activation and antagonism in cardiovascular disease: cellular and molecular mechanisms
2022; Elsevier BV; Volume: 12; Issue: 1 Linguagem: Inglês
10.1016/j.kisu.2021.11.001
ISSN2157-1724
AutoresJohann Bauersachs, Achim Lother,
Tópico(s)Cardiovascular, Neuropeptides, and Oxidative Stress Research
ResumoAldosterone controls salt–water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. However, it is now evident that the MR is expressed in multiple cell types and tissues, acting as a key driver of cardiovascular disease. MR antagonists have proven to be highly efficient in patients with heart failure and reduced ejection fraction, and they are a cornerstone of contemporary therapy. In the past decade, a series of experimental studies using models with cell type–specific MRs uncovered the cellular and molecular mechanisms underlying its detrimental effect on left ventricular remodeling. Based on these findings, the potential of MR antagonists has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction, pulmonary hypertension, atrial fibrillation, and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease. Aldosterone controls salt–water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. However, it is now evident that the MR is expressed in multiple cell types and tissues, acting as a key driver of cardiovascular disease. MR antagonists have proven to be highly efficient in patients with heart failure and reduced ejection fraction, and they are a cornerstone of contemporary therapy. In the past decade, a series of experimental studies using models with cell type–specific MRs uncovered the cellular and molecular mechanisms underlying its detrimental effect on left ventricular remodeling. Based on these findings, the potential of MR antagonists has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction, pulmonary hypertension, atrial fibrillation, and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease. Aldosterone, a steroid hormone produced by zona glomerulosa cells of the adrenal cortex, is a central effector hormone of the renin–angiotensin–aldosterone system.1Lother A. Moser M. Bode C. et al.Mineralocorticoids in the heart and vasculature: new insights for old hormones.Annu Rev Pharmacol Toxicol. 2015; 55: 289-312Google Scholar,2Shibata S. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron.J Endocrinol. 2017; 234: T35-T47Google Scholar The physiological role of aldosterone is to control salt–water homeostasis by acting on the mineralocorticoid receptor (MR), a ligand-activated transcription factor, in kidney epithelial cells. Aldosterone via the MR leads to an upregulation and activation of the amiloride-sensitive epithelial Na+ channel, thereby increasing Na+ reabsorption and K+ secretion.2Shibata S. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron.J Endocrinol. 2017; 234: T35-T47Google Scholar The first MR antagonist (MRA), spironolactone, was developed as an antihypertensive drug, with the intention to prevent Na+ retention and decrease blood volume.3Kolkhof P. Barfacker L. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.J Endocrinol. 2017; 234: T125-T140Google Scholar,4Agarwal R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161Google Scholar However, because of its activity at the progesterone receptor and other nuclear receptors, spironolactone may cause relevant side effects, such as gynecomastia.3Kolkhof P. Barfacker L. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.J Endocrinol. 2017; 234: T125-T140Google Scholar This effect could be ameliorated by the second-generation compound eplerenone and, more recently, a new class of highly selective, potent nonsteroidal MRAs. such as finerenone and esaxerenone.3Kolkhof P. Barfacker L. 30 years of the mineralocorticoid receptor: mineralocorticoid receptor antagonists: 60 years of research and development.J Endocrinol. 2017; 234: T125-T140Google Scholar,4Agarwal R. Kolkhof P. Bakris G. et al.Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine.Eur Heart J. 2021; 42: 152-161Google Scholar The protective cardiovascular effect of MRAs was first attributed to their effects on diuresis, blood volume, and electrolyte homeostasis.5Struthers A.D. Why does spironolactone improve mortality over and above an ACE inhibitor in chronic heart failure?.Br J Clin Pharmacol. 1999; 47: 479-482Google Scholar However, the MR is expressed in multiple cell types and tissues outside the kidney, and it is now evident that MR in extrarenal tissues is a key driver of disease (Figure 1).6Lother A. Mineralocorticoid receptors: master regulators of extracellular matrix remodeling.Circ Res. 2020; 127: 354-356Google Scholar,7Bauersachs J. Jaisser F. Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases.Hypertension. 2015; 65: 257-263Google Scholar More than 20 years ago, major clinical trials provided evidence that MRA treatment improves mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF), leading to a class IA guideline recommendation.8Ponikowski P. Voors A.A. Anker S.D. et al.2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Google Scholar, 9Berliner D. Hanselmann A. Bauersachs J. The treatment of heart failure with reduced ejection fraction.Dtsch Arztebl Int. 2020; 117: 376-386Google Scholar, 10Lother A. Hein L. Pharmacology of heart failure: from basic science to novel therapies.Pharmacol Ther. 2016; 166: 136-149Google Scholar Since then, a series of experimental studies uncovered the cellular and molecular mechanisms underlying the beneficial effect on left ventricular (LV) remodeling. Based on these findings, the potential of MRAs has been evaluated in other cardiovascular diseases, including coronary artery disease, arterial hypertension, heart failure with preserved ejection fraction (HFpEF), pulmonary hypertension (PH), and heart valve disease. The present review summarizes the current knowledge on MR activation and antagonism in cardiovascular disease. MRAs are established drugs in the treatment of chronic HFrEF, as evidenced in multiple studies.8Ponikowski P. Voors A.A. Anker S.D. et al.2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Google Scholar The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) demonstrated a reduction in mortality by 24% in patients with HFrEF and mild symptoms treated with eplerenone versus placebo.11Zannad F. McMurray J.J. Krum H. et al.Eplerenone in patients with systolic heart failure and mild symptoms.N Engl J Med. 2011; 364: 11-21Google Scholar In the Randomized Aldactone Evaluation Study (RALES), spironolactone had a similar effect in patients with severe heart failure symptoms, in whom mortality was reduced by 30% versus placebo.12Pitt B. Zannad F. Remme W.J. et al.The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study investigators.N Engl J Med. 1999; 341: 709-717Google Scholar Studies have shown that, like spironolactone and eplerenone, the nonsteroidal MRA finerenone reduced levels of pro-B-type natriuretic peptide (BNP) or N-terminal BNP (NT-proBNP) in phase II trials.13Pitt B. Kober L. Ponikowski P. et al.Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.Eur Heart J. 2013; 34: 2453-2463Google Scholar,14Filippatos G. Anker S.D. Bohm M. et al.A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease.Eur Heart J. 2016; 37: 2105-2114Google Scholar Early initiation of MRA treatment in patients with acute heart failure was found to be safe and well tolerated.15Butler J. Anstrom K.J. Felker G.M. et al.Efficacy and safety of spironolactone in acute heart failure: the ATHENA-HF randomized clinical trial.JAMA Cardiol. 2017; 2: 950-958Google Scholar,16Asakura M, Ito S, Yamada T, et al. Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure (EARLIER trial): a multicenter, randomized, double-blind, placebo-controlled trial. Eur Heart J Cardiovasc Pharmacother. 2022;8:108–117.Google Scholar Eplerenone improved outcomes of patients with impaired LV function after myocardial infarction (MI).17Pitt B. Remme W. Zannad F. et al.Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 2003; 348: 1309-1321Google Scholar Subsequent studies tested the hypothesis that initiation of MR blockade early after MI might prevent cardiac remodeling and the occurrence of heart failure. When initiated within 72 hours after symptom onset, MRA treatment improved BNP/NT-proBNP levels in patients without preexisting heart failure.18Montalescot G. Pitt B. Lopez de Sa E. et al.Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study.Eur Heart J. 2014; 35: 2295-2302Google Scholar However, in a later study, a potential benefit of early MRA treatment on clinical outcomes was observed only in the subgroup of high-risk patients with ST-elevation MI.19Beygui F. Cayla G. Roule V. et al.Early aldosterone blockade in acute myocardial infarction: the ALBATROSS randomized clinical trial.J Am Coll Cardiol. 2016; 67: 1917-1927Google Scholar An individual patient-level meta-analysis of 3 large randomized controlled trials in patients with HFrEF also demonstrated a 23% reduction in sudden cardiac death with MRA treatment.20Rossello X. Ariti C. Pocock S.J. et al.Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials.Clin Res Cardiol. 2019; 108: 477-486Google Scholar In patients with newly diagnosed HFrEF, treatment with higher MRA dosages was associated with superior amelioration of LV ejection fraction beyond 3 months.21Duncker D. Konig T. Hohmann S. et al.Avoiding untimely implantable cardioverter/defibrillator implantation by intensified heart failure therapy optimization supported by the wearable cardioverter/defibrillator–the PROLONG study.J Am Heart Assoc. 2017; 6e004512Google Scholar Experimental studies using MRAs in animal models of heart failure and post-MI remodeling demonstrated beneficial effects on cardiac hypertrophy, fibrosis, or both (Figure 1).22Kuster G.M. Kotlyar E. Rude M.K. et al.Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload.Circulation. 2005; 111: 420-427Google Scholar, 23Fraccarollo D. Galuppo P. Schmidt I. et al.Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction.Cardiovasc Res. 2005; 67: 97-105Google Scholar, 24Fraccarollo D. Galuppo P. Schraut S. et al.Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response.Hypertension. 2008; 51: 905-914Google Scholar, 25Gueret A. Harouki N. Favre J. et al.Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction.Hypertension. 2016; 67: 717-723Google Scholar Subsequently, the use of mouse models with cell-specific MR deletion provided evidence that these effects were mediated by MR activation in cardiovascular cells. MR deletion from cardiac myocytes resulted in smaller scar size, less fibrosis of the remote tissue, and improved LV function.26Fraccarollo D. Berger S. Galuppo P. et al.Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.Circulation. 2011; 123: 400-408Google Scholar Reduced fibrosis after ischemic injury was associated with attenuated oxidative stress and myocyte apoptosis, but higher numbers of neutrophils and monocytes were detected in myocardial tissue from MR-deficient mice compared with wild-type mice.26Fraccarollo D. Berger S. Galuppo P. et al.Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.Circulation. 2011; 123: 400-408Google Scholar Notably, MR deletion from myeloid cells likewise improved LV remodeling and induced a shift toward the more-reparative M2 macrophage subtype.27Fraccarollo D. Thomas S. Scholz C.J. et al.Macrophage mineralocorticoid receptor is a pleiotropic modulator of myocardial infarct healing.Hypertension. 2019; 73: 102-111Google Scholar MR deletion from smooth muscle cells (SMCs) attenuated LV fibrosis but had minor effects on LV function.25Gueret A. Harouki N. Favre J. et al.Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction.Hypertension. 2016; 67: 717-723Google Scholar This implies that MRAs have effects on different cell types that synergistically contribute to damage control and healing after MI. The centrality of inflammation in mediating the deleterious effect of MR activation has been confirmed in models of chronic heart failure (Figure 2).25Gueret A. Harouki N. Favre J. et al.Vascular smooth muscle mineralocorticoid receptor contributes to coronary and left ventricular dysfunction after myocardial infarction.Hypertension. 2016; 67: 717-723Google Scholar, 26Fraccarollo D. Berger S. Galuppo P. et al.Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.Circulation. 2011; 123: 400-408Google Scholar, 27Fraccarollo D. Thomas S. Scholz C.J. et al.Macrophage mineralocorticoid receptor is a pleiotropic modulator of myocardial infarct healing.Hypertension. 2019; 73: 102-111Google Scholar, 28Li C. Zhang Y.Y. Frieler R.A. et al.Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.PLoS One. 2014; 9e110950Google Scholar, 29Usher M.G. Duan S.Z. Ivaschenko C.Y. et al.Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.J Clin Invest. 2010; 120: 3350-3364Google Scholar, 30Li C. Sun X.N. Zeng M.R. et al.Mineralocorticoid receptor deficiency in T cells attenuates pressure overload-induced cardiac hypertrophy and dysfunction through modulating T-Cell activation.Hypertension. 2017; 70: 137-147Google Scholar, 31Kim S.K. Biwer L.A. Moss M.E. et al.Mineralocorticoid receptor in smooth muscle contributes to pressure overload-induced heart failure.Circ Heart Fail. 2021; 14e007279Google Scholar, 32Lother A. Berger S. Gilsbach R. et al.Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function.Hypertension. 2011; 57: 746-754Google Scholar, 33Salvador A.M. Moss M.E. Aronovitz M. et al.Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation.Physiol Rep. 2017; 5: e13313Google Scholar, 34Lother A. Hein L. Vascular mineralocorticoid receptors: linking risk factors, hypertension, and heart disease.Hypertension. 2016; 68: 6-10Google Scholar, 35Jia G. Habibi J. DeMarco V.G. et al.Endothelial mineralocorticoid receptor deletion prevents diet-induced cardiac diastolic dysfunction in females.Hypertension. 2015; 66: 1159-1167Google Scholar, 36Rickard A.J. Morgan J. Chrissobolis S. et al.Endothelial cell mineralocorticoid receptors regulate deoxycorticosterone/salt-mediated cardiac remodeling and vascular reactivity but not blood pressure.Hypertension. 2014; 63: 1033-1040Google Scholar, 37Rickard A.J. Morgan J. Tesch G. et al.Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure.Hypertension. 2009; 54: 537-543Google Scholar, 38Bienvenu L.A. Morgan J. Rickard A.J. et al.Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis.Endocrinology. 2012; 153: 3416-3425Google Scholar, 39Moss M.E. Lu Q. Iyer S.L. et al.Endothelial mineralocorticoid receptors contribute to vascular inflammation in atherosclerosis in a sex-specific manner.Arterioscler Thromb Vasc Biol. 2019; 39: 1588-1601Google Scholar, 40Shen Z.X. Chen X.Q. Sun X.N. et al.Mineralocorticoid receptor deficiency in macrophages inhibits atherosclerosis by affecting foam cell formation and efferocytosis.J Biol Chem. 2017; 292: 925-935Google Scholar, 41Moss M.E. DuPont J.J. Iyer S.L. et al.No significant role for smooth muscle cell mineralocorticoid receptors in atherosclerosis in the apolipoprotein-E knockout mouse model.Front Cardiovasc Med. 2018; 5: 81Google Scholar, 42Pruthi D. McCurley A. Aronovitz M. et al.Aldosterone promotes vascular remodeling by direct effects on smooth muscle cell mineralocorticoid receptors.Arterioscler Thromb Vasc Biol. 2014; 34: 355-364Google Scholar, 43Sun J.Y. Li C. Shen Z.X. et al.Mineralocorticoid receptor deficiency in macrophages inhibits neointimal hyperplasia and suppresses macrophage inflammation through SGK1-AP1/NF-kappaB pathways.Arterioscler Thromb Vasc Biol. 2016; 36: 874-885Google Scholar, 44Barrett Mueller K. Bender S.B. Hong K. et al.Endothelial mineralocorticoid receptors differentially contribute to coronary and mesenteric vascular function without modulating blood pressure.Hypertension. 2015; 66: 988-997Google Scholar, 45Laursen S.B. Finsen S. Marcussen N. et al.Endothelial mineralocorticoid receptor ablation does not alter blood pressure, kidney function or renal vessel contractility.PLoS One. 2018; 13e0193032Google Scholar, 46McCurley A. Pires P.W. Bender S.B. et al.Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors.Nat Med. 2012; 18: 1429-1433Google Scholar, 47DuPont J.J. McCurley A. Davel A.P. et al.Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging.JCI Insight. 2016; 1: e88942Google Scholar, 48Galmiche G. Pizard A. Gueret A. et al.Smooth muscle cell mineralocorticoid receptors are mandatory for aldosterone-salt to induce vascular stiffness.Hypertension. 2014; 63: 520-526Google Scholar, 49Sun X.N. Li C. Liu Y. et al.T-cell mineralocorticoid receptor controls blood pressure by regulating interferon-gamma.Circ Res. 2017; 120: 1584-1597Google Scholar, 50Kowalski J. Deng L. Suennen C. et al.Eplerenone improves pulmonary vascular remodeling and hypertension by inhibition of the mineralocorticoid receptor in endothelial cells.Hypertension. 2021; 78: 456-465Google Scholar, 51Lother A. Bergemann S. Kowalski J. et al.Inhibition of the cardiac myocyte mineralocorticoid receptor ameliorates doxorubicin-induced cardiotoxicity.Cardiovasc Res. 2018; 114: 282-290Google Scholar, 52Yi Y. Du L. Qin M. et al.Regulation of atrial fibrosis by the bone.Hypertension. 2019; 73: 379-389Google Scholar, 53Ibarrola J. Garcia-Pena A. Matilla L. et al.A new role for the aldosterone/mineralocorticoid receptor pathway in the development of mitral valve prolapse.Circ Res. 2020; 127: e80-e93Google Scholar, 54Lother A. Deng L. Huck M. et al.Endothelial cell mineralocorticoid receptors oppose VEGF-induced gene expression and angiogenesis.J Endocrinol. 2019; 240: 15-26Google Scholar MR deletion from myeloid cells prevented cardiac remodeling in response to pressure overload or N(G)-nitro-L-arginine methyl ester (L-NAME)/angiotensin II infusion.28Li C. Zhang Y.Y. Frieler R.A. et al.Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.PLoS One. 2014; 9e110950Google Scholar,29Usher M.G. Duan S.Z. Ivaschenko C.Y. et al.Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.J Clin Invest. 2010; 120: 3350-3364Google Scholar Similar effects were observed in mice lacking MRs in T cells.30Li C. Sun X.N. Zeng M.R. et al.Mineralocorticoid receptor deficiency in T cells attenuates pressure overload-induced cardiac hypertrophy and dysfunction through modulating T-Cell activation.Hypertension. 2017; 70: 137-147Google Scholar Very recently, SMC MR deletion was shown to improve pressure overload–induced LV hypertrophy, inflammation, fibrosis, and dysfunction.31Kim S.K. Biwer L.A. Moss M.E. et al.Mineralocorticoid receptor in smooth muscle contributes to pressure overload-induced heart failure.Circ Heart Fail. 2021; 14e007279Google Scholar MR deletion from endothelial cells or cardiac myocytes improved LV function, but in contrast to ischemic injury, it did not regulate fibrosis after pressure overload.32Lother A. Berger S. Gilsbach R. et al.Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function.Hypertension. 2011; 57: 746-754Google Scholar,33Salvador A.M. Moss M.E. Aronovitz M. et al.Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation.Physiol Rep. 2017; 5: e13313Google Scholar No differences were detected after MR deletion from fibroblasts.32Lother A. Berger S. Gilsbach R. et al.Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function.Hypertension. 2011; 57: 746-754Google Scholar These findings suggest that the impact of the MR on cardiac remodeling depends on not only the cell type but also the type of injury. Substantial efforts have been made to decipher molecular regulatory mechanisms behind aldosterone/MR-induced LV remodeling. Well-characterized inflammatory and fibrotic effector molecules of the MR in the cardiovascular system include galectin 3 (LGALS3) and lipocalin 2 (NGAL).55Calvier L. Martinez-Martinez E. Miana M. et al.The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Google Scholar, 56Martinez-Martinez E. Calvier L. Fernandez-Celis A. et al.Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.Hypertension. 2015; 66: 767-775Google Scholar, 57Tarjus A. Martinez-Martinez E. Amador C. et al.Neutrophil gelatinase-associated lipocalin, a novel mineralocorticoid biotarget, mediates vascular profibrotic effects of mineralocorticoids.Hypertension. 2015; 66: 158-166Google Scholar, 58Buonafine M. Martinez-Martinez E. Amador C. et al.Neutrophil gelatinase-associated lipocalin from immune cells is mandatory for aldosterone-induced cardiac remodeling and inflammation.J Mol Cell Cardiol. 2018; 115: 32-38Google Scholar Intriguingly, pharmacologic inhibition by modified citrus pectin or genetic deletion of galectin 3 attenuated aldosterone-induced cardiac remodeling.55Calvier L. Martinez-Martinez E. Miana M. et al.The impact of galectin-3 inhibition on aldosterone-induced cardiac and renal injuries.JACC Heart Fail. 2015; 3: 59-67Google Scholar,56Martinez-Martinez E. Calvier L. Fernandez-Celis A. et al.Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.Hypertension. 2015; 66: 767-775Google Scholar Plasma levels of NGAL were positively correlated with circulating aldosterone levels and fibrosis biomarkers in humans.57Tarjus A. Martinez-Martinez E. Amador C. et al.Neutrophil gelatinase-associated lipocalin, a novel mineralocorticoid biotarget, mediates vascular profibrotic effects of mineralocorticoids.Hypertension. 2015; 66: 158-166Google Scholar Deletion of NGAL from immune cells prevented LV fibrosis in response to aldosterone infusion.58Buonafine M. Martinez-Martinez E. Amador C. et al.Neutrophil gelatinase-associated lipocalin from immune cells is mandatory for aldosterone-induced cardiac remodeling and inflammation.J Mol Cell Cardiol. 2018; 115: 32-38Google Scholar Likewise, MR deletion from myeloid cells improved cardiac remodeling after myocardial infarction, which was associated with reduced NGAL expression in cardiac macrophages.27Fraccarollo D. Thomas S. Scholz C.J. et al.Macrophage mineralocorticoid receptor is a pleiotropic modulator of myocardial infarct healing.Hypertension. 2019; 73: 102-111Google Scholar A recent high-throughput screening of microRNAs identified miR-181a as a crucial regulator of MR signaling.59Garg A. Foinquinos A. Jung M. et al.MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptor-mediated cardiac remodelling.Eur J Heart Fail. 2020; 22: 1366-1377Google Scholar miR-181a overexpression downregulated NGAL expression in vitro and in vivo and improved cardiac function in a rodent MI model.59Garg A. Foinquinos A. Jung M. et al.MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptor-mediated cardiac remodelling.Eur J Heart Fail. 2020; 22: 1366-1377Google Scholar The prevalence of HFpEF is increasing and already accounts for more than 50% of heart failure cases.60Gladden J.D. Chaanine A.H. Redfield M.M. Heart failure with preserved ejection fraction.Annu Rev Med. 2018; 69: 65-79Google Scholar Despite overlapping symptoms, HFpEF is considered to be a separate entity from HFrEF.60Gladden J.D. Chaanine A.H. Redfield M.M. Heart failure with preserved ejection fraction.Annu Rev Med. 2018; 69: 65-79Google Scholar Compared with patients with HFrEF, patients with HFpEF are older, more often female and obese, and have more comorbidities, such as diabetes and kidney disease, that are associated with chronic inflammation.60Gladden J.D. Chaanine A.H. Redfield M.M. Heart failure with preserved ejection fraction.Annu Rev Med. 2018; 69: 65-79Google Scholar,61Paulus W.J. Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.J Am Coll Cardiol. 2013; 62: 263-271Google Scholar MR activation increases oxidative stress and impairs nitric oxide (NO) signaling, leading to endothelial dysfunction, inflammation, and perivascular fibrosis.34Lother A. Hein L. Vascular mineralocorticoid receptors: linking risk factors, hypertension, and heart disease.Hypertension. 2016; 68: 6-10Google Scholar Although the ideal preclinical model to study HFpEF remains to be defined, a clear finding is that MR activation is associated with many of the pathophysiological features that characterize HFpEF.62Valero-Munoz M. Backman W. Sam F. Murine models of heart failure with preserved ejection fraction: a "fishing expedition.".JACC Basic Transl Sci. 2017; 2: 770-789Google Scholar,63Riehle C. Bauersachs J. Small animal models of heart failure.Cardiovasc Res. 2019; 115: 1838-1849Google Scholar MRAs improved diastolic dysfunction induced by obesity, ovariectomy, nephrectomy, or deoxycorticosterone acetate (DOCA)/salt hypertension in mice.64Bender S.B. DeMarco V.G. Padilla J. et al.Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction.Hypertension. 2015; 65: 1082-1088Google Scholar, 65Pieronne-Deperrois M. Gueret A. Djerada Z. et al.Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.ESC Heart Fail. 2021; 8: 1933-1943Google Scholar, 66Bonnard B. Pieronne-Deperrois M. Djerada Z. et al.Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice.J Mol Cell Cardiol. 2018; 121: 124-133Google Scholar, 67Brown L. Duce B. Miric G. et al.Reversal of cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats by inhibition of the renin-angiotensin system.J Am Soc Nephrol. 1999; 10: S143-S148Google Scholar Cell type–specific MR deletion from cardiac myocytes attenuated leukocyte invasion and fibrosis after DOCA treatment.68Rickard A.J. Morgan J. Bienvenu L.A. et al.Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis.Hypertension. 2012; 60: 1443-1450Google Scholar In line with the paradigm of systemic inflammation in HFpEF, MR deletion from endothelial cells or myeloid cells demonstrated the most striking effect on cardiac remodeling (Figure 2).35Jia G. Habibi J. DeMarco V.G. et al.Endothelial mineralocorticoid receptor deletion prevents diet-induced cardiac diastolic dysfunction in females.Hypertension. 2015; 66: 1159-
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