these data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism.

Intermittent hypoxia (IH) commonly occurs in patients with obstructive sleep apnea and can cause a wide range of pathology, including reduced left ventricular (LV) ejection fraction in rats as determined by echocardiography, in rodent models. We utilized echocardiography and pressure-volume (PV) loop analyses to determine whether LV contractility was decreased in inbred C57BL/6J mice exposed to IH and whether blockade of beta-adrenergic receptors modified the response to hypoxia. Adult male 9- to 10-wk-old mice were exposed to 4 wk of IH (nadir inspired O(2) 5-6% at 60 cycles/h for 12 h during the light period) or intermittent air (IA) as control. A second group of animals were exposed to the same regimen of IH or IA, but in the presence of nonspecific beta-blockade with propranolol. Cardiac function was assessed by echocardiography and PV loop analyses, and mRNA and protein expression in ventricular homogenates was determined. Contrary to our expectations, we found with PV loop analyses that LV ejection fraction (63.4 +/- 3.5 vs. 50.5 +/- 2.6%, P = 0.015) and other measures of LV contractility were increased in IH-exposed animals compared with IA controls. There were no changes in contractile proteins, atrial natriuretic peptide levels, LV posterior wall thickness, or heart weight with IH exposure. However, cAMP levels were elevated after IH, and propranolol administration attenuated the increase in LV contractility induced by IH exposure. We conclude that, contrary to our hypothesis, 4 wk of IH exposure in C57BL/6J mice causes an increase in LV contractility that occurs independent of ventricular hypertrophy and is, in part, mediated by activation of cardiac beta-adrenergic pathways.

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Background: The expression of cardiac sodium/glucose cotransporter 1 (SGLT1) is up-regulated in ischemic heart disease. However, the regulation and the biological role of SGLT1 activity in cardiomyocytes are unclear. Hypothesis: We hypothesize that SGLT1 inhibition during ischemia-reperfusion (IR) will lead to worsening cardiac function and recovery. In addition we hypothesize that SGLT1 expression is upregulated by increased AMPK activity in ischemia. Methods: Transgenic mice with cardiac-specific RNAi knockdown of SGLT1 (TG SGLT1-KD ) were subjected to ex vivo IR (n > 3/group) using a Langendorff hanging heart preparation with 15 min of no-flow ischemia and 20 min of reperfusion while undergoing hemodynamic monitoring. FVB strain wild-type 8-12 week-old male mice (n > 3/group) were administered either the SGLT1 inhibitor phlorizin (400 mg/kg IP) or vehicle and subjected to in vivo ischemia for 30 min by ligation of the left anterior descending (LAD) coronary artery. Hearts were harvested 48 hours later. In vitro studies were conducted in HL-1 cardiomyocytes subjected to 1 h of simulated ischemia with 1 mM NaCN. HL-1 cells were also treated with 1 mM AICAR, an AMPK activator, for 16 hours and SGLT1 expression was measured. Results: In ex vivo IR studies, there was an impairment in the early recovery of double product in the TG SGLT1-KD mice compared to control mice (37% vs 92% at 1 min into reperfusion, P < 0.05). In in vivo IR studies, phlorizin led to a marked increase in oxidative stress documented by cardiac malondialdehyde (MDA) (control 1.00±0.00; IR 1.55±0.35; IR + phlorizin 16.15±0.40, P <0.001),an increase in apoptosis documented by TUNEL staining, and hemodynamic impairment: +dP/dt (mmHg/sec), control 11445±504, IR 9811±2613, IR + phlorizin 5139±481, P <0.05; -dP/dt (mmHg/sec), control -10625±589, IR -6770±1142, IR + phlorizin -4153±474, P <0.05. In HL-1 cardiomyocytes, there was a 6.7-fold increase in SGLT1 expression after simulated ischemia, and a 2.0-fold increase after AICAR exposure. Conclusion: SGLT1 expression increases when cardiomyocytes are subjected to ischemia, an effect that may be mediated by AMPK. Inhibition of SGLT1 leads to impaired myocardial recovery from ischemia.