Aldosterone Production Is Activated in Failing Ventricle in Humans

Mizuno, Yuji; Yoshimura, Michihiro; Yasue, Hirofumi; Sakamoto, Tomohiro; Ogawa, Hisao; Kugiyama, Kiyotaka; Harada, Eisaku; Nakayama, Masafumi; Nakamura, Shota; Ito, Taeko; Shimasaki, Yukio; Saito, Yoshihiko; Nakao, Kazuwa

doi:10.1161/01.cir.103.1.72

Cited by 319 publications

(203 citation statements)

References 35 publications

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“…This thesis is supported by the observations that cardiac myocytes express mineralocorticoid receptors 35 and that aldosterone is synthesized by the myocardium, 36 as well as by studies in which elevated aldosterone levels were associated with adverse myocardial remodeling (hypertrophy, fibrosis, and LV dilation) that was inhibited by a mineralocorticoid receptor antagonist. 6 -10,13 It should also be noted that, under appropriate conditions, glucocorticoids may lead to mineralocorticoid receptor activation in the cardiac myocyte.…”

Section: Discussion Mineralocorticoid Receptor Activation Is Involvedmentioning

confidence: 73%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

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Section: Discussion Mineralocorticoid Receptor Activation Is Involvedmentioning

confidence: 73%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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“…Aldosterone synthase (CYP11B2) is detected in the hearts of several species, including rats 9,10 and humans. 11,12 Cardiac aldosterone production has also been found in experiments demonstrating a gradient of plasma aldosterone concentrations between the anterior interventricular vein and coronary sinus in humans, 13,14 and myocardial production of aldosterone has been demonstrated in the rat. 15 Increased production of cardiac aldosterone under certain pathological conditions suggests that it could play an important role in the pathogenesis of cardiac diseases.…”

mentioning

confidence: 76%

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

et al. 2005

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Background-The renin-angiotensin-aldosterone system is implicated in the pathogenesis of heart failure. Pharmacological blockade of angiotensin II (Ang II)-dependent signaling is clinically effective in reducing cardiovascular events after myocardial infarction (MI) but still fails to completely prevent remodeling. The molecular basis underlying this Ang II-independent remodeling is unclear. Methods and Results-Acute MI was induced by coronary ligation in wild-type (WT) and angiotensin II type IA receptor-knockout (AT 1A -KO) mice. Left ventricular (LV) geometry, hemodynamics, and cardiac gene expression were evaluated on day 28. Severe LV remodeling and resultant cardiac dysfunction were observed in WT mice, whereas less marked, but still significant, LV remodeling and cardiac dysfunction were induced in AT 1A -KO mice. Gene expression levels of aldosterone synthase and the cardiac aldosterone content were both elevated in the MI hearts, even in AT 1A -KO mice. In AT 1A -KO mice treated with spironolactone (20 mg/kg per day), LV remodeling, cardiac dysfunction, and cardiac gene expression of collagens and natriuretic peptides were almost normalized. Conclusions-Our results indicate that genetic blockade of AT 1A signaling fails to arrest aldosterone production in cardiac tissues and that cardiac aldosterone plays a critical role in post-MI LV remodeling. The results suggest that spironolactone could be potentially effective in patients with MI, when used in combination with renin-angiotensin system blockade, by blocking the actions of aldosterone produced by Ang II-independent mechanisms. (Circulation. 2005;111:2157-2164.)

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“…However, the pathophysiological significance of the increase (even by a small amount) in aldosterone levels both in circulation and local tissue, as well as its cascade activation in severe heart diseases (Mizuno et al 2001, Nakamura et al 2004, such as myocardial infarction (Beygui et al 2006), has not yet been fully clarified.…”

Section: Introductionmentioning

confidence: 99%

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Yoshino¹,

Nagoshi²,

Anzawa³

et al. 2014

Journal of Endocrinology

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Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia-reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10 K9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia-reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemiareperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia-reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

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Aldosterone Production Is Activated in Failing Ventricle in Humans

Cited by 319 publications

References 35 publications

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor–Knockout Mice After Myocardial Infarction

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

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