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

Abstract

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.

Mineralocorticoid Receptor Blockade Improves Insulin Sensitivity in the Rat Heart and a Possible Molecular Mechanism

“…In our study, we found that aldosterone inhibited PPARα and adiponectin protein expression and promoted inflammation and insulin resistance in cardiomyocytes; however, in contrast to muscle cells, p38MAPK protein expression was increased in the cardiomyocytes. MR blockade with eplerenone reversed these effects, and this finding accords with those of recent studies that demonstrated that aldosterone stimulates the p38MAPK signaling pathway in rat podocytes [32] and that the inhibition of PPARα increases IL-18 expression in cardiomyocytes [33]. Therefore, it is possible that p38MAPK and PPARα are both involved in MR-induced adiponectin expression in cardiomyocytes.…”

Expression of SGLT1 in Human Hearts and Impairment of Cardiac Glucose Uptake by Phlorizin during Ischemia-Reperfusion Injury in Mice

“…in order to eliminate suffering. The heart was then rapidly excised, and the aorta was cannulated onto a Langendorff apparatus, followed by retrograde-perfusion at a constant pressure (80 mmHg) with modified Krebs-Henseleit buffer, as previously described [ 3 , 13 – 15 ]. A water-filled balloon catheter was introduced into the left ventricle to record various hemodynamic parameters.…”

Cardiac ischemia–reperfusion injury under insulin-resistant conditions: SGLT1 but not SGLT2 plays a compensatory protective role in diet-induced obesity

“…in order to eliminate suffering. The heart was then rapidly excised, and the aorta was cannulated onto a Langendorff apparatus, followed by retrograde-perfusion at a constant pressure (80 mmHg) with modified Krebs-Henseleit buffer (11 mM glucose, 118 mM NaCl, 4.7 mM KCl, 2.0 mM CaCl 2 , 1.2 mM MgSO 4 , 1.2 mM KH 2 PO 4 , 25 mM NaHCO 3 , 0.5 mM EDTA), as previously described [7,11,26]. A temperature-regulated heart chamber was then placed around the heart in order to keep the perfused heart at a certain temperature.…”

“…Creatine phosphokinase (CPK) levels were measured in the effluent using an enzymatic activity assay, as previously described [7,26]. Values were corrected for coronary flow and heart weight [CPK (U/l) × coronary flow (l/min)/heart weight (g) = U/min/g].…”

“…Immunoblotting was performed as previously described [7,[26][27][28] with rabbit polyclonal anti-SGLT1 (1:200, #H-85; Santa Cruz Biotechnology, CA, USA), anti-GLUT4 (1:1000, #ab33780; Abcam, Cambridge, MA, USA), anti-GLUT1 (1:1000, #12939; Cell Signaling Technology, Tokyo, Japan), or mouse monoclonal anti-α1 Na-K-ATPase (1:1000, #ab7671; Abcam). The signals were detected using chemiluminescence.…”