Losartan treatment attenuates tumor-induced myocardial dysfunction.

UNLABELLED: Fatigue and muscle wasting are common symptoms experienced by cancer patients. Data from animal models demonstrate that angiotensin is involved in tumor-induced muscle wasting, and that tumor growth can independently affect myocardial function, which could contribute to fatigue in cancer patients. In clinical studies, inhibitors of angiotensin converting enzyme (ACE) can prevent the development of chemotherapy-induced cardiovascular dysfunction, suggesting a mechanistic role for the renin-angiotensin-aldosterone system (RAAS). In the present study, we investigated whether an angiotensin (AT) 1-receptor antagonist could prevent the development of tumor-associated myocardial dysfunction. METHODS AND RESULTS: Colon26 adenocarcinoma (c26) cells were implanted into female CD2F1 mice at 8weeks of age. Simultaneously, mice were administered Losartan (10mg/kg) daily via their drinking water. In vivo echocardiography, blood pressure, in vitro cardiomyocyte function, cell proliferation assays, and measures of systemic inflammation and myocardial protein degradation were performed 19days following tumor cell injection. Losartan treatment prevented tumor-induced loss of muscle mass and in vitro c26 cell proliferation, decreased tumor weight, and attenuated myocardial expression of interleukin-6. Furthermore, Losartan treatment mitigated tumor-associated alterations in calcium signaling in cardiomyocytes, which was associated with improved myocyte contraction velocity, systolic function, and blood pressures in the hearts of tumor-bearing mice. CONCLUSIONS: These data suggest that Losartan may mitigate tumor-induced myocardial dysfunction and inflammation.

Metabolic dysfunction in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is defined as cardiac disease independent of vascular complications during diabetes. The number of new cases of DCM is rising at epidemic rates in proportion to newly diagnosed cases of diabetes mellitus (DM) throughout the world. DCM is a heart failure syndrome found in diabetic patients that is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction, occurring in the absence of hypertension and coronary artery disease. DCM and other diabetic complications are caused in part by elevations in blood glucose and lipids, characteristic of DM. Although there are pathological consequences to hyperglycemia and hyperlipidemia, the combination of the two metabolic abnormalities potentiates the severity of diabetic complications. A natural competition exists between glucose and fatty acid metabolism in the heart that is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes. Inhibition of these glycolytic enzymes not only controls flux of substrate through the glycolytic pathway, but also leads to the diversion of glycolytic intermediate substrate through pathological pathways, which mediate the onset of diabetic complications. The present review describes the limiting steps involved in the development of these pathological pathways and the factors involved in the regulation of these limiting steps. Additionally, therapeutic options with demonstrated or postulated effects on DCM are described.

Arrhythmogenic adverse effects of cardiac glycosides are mediated by redox modification of ryanodine receptors.

The therapeutic use of cardiac glycosides (CGs), agents commonly used in treating heart failure (HF), is limited by arrhythmic toxicity. The adverse effects of CGs have been attributed to excessive accumulation of intracellular Ca(2+) resulting from inhibition of Na(+)/K(+)-ATPase ion transport activity. However, CGs are also known to increase intracellular reactive oxygen species (ROS), which could contribute to arrhythmogenesis through redox modification of cardiac ryanodine receptors (RyR2s). Here we sought to determine whether modification of RyR2s by ROS contributes to CG-dependent arrhythmogenesis and examine the relevant sources of ROS. In isolated rat ventricular myocytes, the CG digitoxin (DGT) increased the incidence of arrhythmogenic spontaneous Ca(2+) waves, decreased the sarcoplasmic reticulum (SR) Ca(2+) load, and increased both ROS and RyR2 thiol oxidation. Additionally, pretreatment with DGT increased spark frequency in permeabilized myocytes. These effects on Ca(2+) waves and sparks were prevented by the antioxidant N-(2-mercaptopropionyl) glycine (MPG). The CG-dependent increases in ROS, RyR2 oxidation and arrhythmogenic propensity were reversed by inhibitors of NADPH oxidase, mitochondrial ATP-dependent K(+) channels (mito-K(ATP)) or permeability transition pore (PTP), but not by inhibition of xanthine oxidase. These results suggest that the arrhythmogenic adverse effects of CGs involve alterations in RyR2 function caused by oxidative changes in the channel structure by ROS. These CG-dependent effects probably involve release of ROS from mitochondria possibly mediated by NADPH oxidase.

Intra-sarcoplasmic reticulum Ca2+ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca2+ in cardiomyocytes.

During the cardiac cycle, the release of Ca(2+) from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR2) channel complex is controlled by the levels of cytosolic and luminal Ca(2+) and alterations in these regulatory processes have been implicated in cardiac disease including arrhythmia. To better understand the mechanisms of regulation of SR Ca(2+) release by Ca(2+) on both sides of the SR membrane, we investigated SR Ca(2+) release in a wide range of cytosolic Ca(2+) concentrations ([Ca(2+)](cyt); 1-100 microm) in permeabilized canine ventricular myocytes by monitoring [Ca(2+)] inside the SR ([Ca(2+)](SR)). Exposing myocytes to activating [Ca(2+)](cyt) resulted in spontaneous oscillations of [Ca(2+)](SR) due to periodic opening and closing of the RyR2s. Elevating [Ca(2+)](cyt) (up to 10 microm) increased the frequency of [Ca(2+)](SR) oscillations; however at higher [Ca(2+)](cyt) (>50 microm) the oscillations diminished due to RyR2s staying perpetually open, resulting in depleted SR. Ablation of cardiac calsequestrin (CASQ2) altered the [Ca(2+)](cyt) dependence of Ca(2+) release oscillations such that oscillations were highly frequent at low [Ca(2+)](cyt) (100 nm) but became diminished at moderate [Ca(2+)](cyt) (10 microm), as determined in myocytes from calsequestrin-null versus wild-type mice. Our results suggest that under conditions of continuous activation by cytosolic Ca(2+), RyR2s can periodically cycle between open and deactivated states due to effects of luminal Ca(2+). Deactivation at reduced [Ca(2+)]SR appears to involve reduction of sensitivity to cytosolic Ca(2+) and might be mediated by CASQ2. Inactivation by cytosolic Ca(2+) plays no detectable role in controlling SR Ca(2+) release.