Activation of Pak1/Akt/eNOS signaling following sphingosine-1-phosphate release as part of a mechanism protecting cardiomyocytes against ischemic cell injury.

We investigated whether plasma long-chain sphingoid base (LCSB) concentrations are altered by transient cardiac ischemia during percutaneous coronary intervention (PCI) in humans and examined the signaling through the sphingosine-1-phosphate (S1P) cascade as a mechanism underlying the S1P cardioprotective effect in cardiac myocytes. Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) of 31 patients at 1 and 5 min and 12 h, following induction of transient myocardial ischemia during elective PCI. Coronary sinus levels of LCSB were increased by 1,072% at 1 min and 941% at 5 min (n = 7), while peripheral blood levels of LCSB were increased by 579% at 1 min, 617% at 5 min, and 436% at 12 h (n = 24). In cultured cardiac myocytes, S1P, sphingosine (SPH), and FTY720, a sphingolipid drug candidate, showed protective effects against CoCl induced hypoxia/ischemic cell injury by reducing lactate dehydrogenase activity. Twenty-five nanomolars of FTY720 significantly increased phospho-Pak1 and phospho-Akt levels by 56 and 65.6% in cells treated with this drug for 15 min. Further experiments demonstrated that FTY720 triggered nitric oxide release from cardiac myocytes is through pertussis toxin-sensitive phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase signaling. In ex vivo hearts, ischemic preconditioning was cardioprotective in wild-type control mice (Pak1(f/f)), but this protection appeared to be ineffective in cardiomyocyte-specific Pak1 knockout (Pak1(cko)) hearts. The present study provides the first direct evidence of the behavior of plasma sphingolipids following transient cardiac ischemia with dramatic and early increases in LCSB in humans. We also demonstrated that S1P, SPH, and FTY720 have protective effects against hypoxic/ischemic cell injury, likely a Pak1/Akt1 signaling cascade and nitric oxide release. Further study on a mouse model of cardiac specific deletion of Pak1 demonstrates a crucial role of Pak1 in cardiac protection against ischemia/reperfusion injury.

A review of thiazide-induced hyponatraemia.

There are numerous reports of thiazide-induced hyponatraemia (TIH) and its incidence is growing as a result of increasing prescription after guidelines recommending thiazides as first-line treatment of essential hypertension have been introduced. Thiazide diuretics are a common cause of severe hyponatraemia that is usually induced within two weeks of starting the thiazide diuretic, but it can occur any time and very rapidly in susceptible patients. Despite several relevant reports and years of clinical experience, TIH remains a very common clinical scenario. Although its impact has recently been reviewed, little attention has been given to the practical approach for preventing this medical complication. In the present review, the epidemiology, pathogenesis, clinical presentation and management of TIH are discussed, and an approach to its prevention suggested in the hope that increased awareness and understanding will reduce the incidence and complications of this potentially life-threatening condition.

Serum sphingolipids level as a novel potential marker for early detection of human myocardial ischaemic injury.

BACKGROUND: Ventricular tachyarrhythmias are the most common and often the first manifestation of coronary heart disease and lead to sudden cardiac death (SCD). Early detection/identification of acute myocardial ischaemic injury at risk for malignant ventricular arrhythmias in patients remains an unmet medical need. In the present study, we examined the sphingolipids level after transient cardiac ischaemia following temporary coronary artery occlusion during percutaneous coronary intervention (PCI) in patients and determined the role of sphingolipids level as a novel marker for early detection of human myocardial ischaemic injury. METHODS AND RESULTS: Venous samples were collected from either the coronary sinus (n = 7) or femoral vein (n = 24) from 31 patients aged 40-73 years-old at 1, 5 min, and 12 h, following elective PCI. Plasma sphingolipids levels were assessed by HPLC. At 1 min coronary sinus levels of sphingosine 1-phosphate (S1P), sphingosine (SPH), and sphinganine (SA) were increased by 314, 115, and 614%, respectively (n = 7), while peripheral blood levels increased by 79, 68, and 272% (n = 24). By 5 min, coronary sinus S1P and SPH levels increased further (720%, 117%), as did peripheral levels of S1P alone (792%). Where troponin T was detectable at 12 h (10 of 31), a strong correlation was found with peak S1P (R (2) = 0.818; P < 0.0001). CONCLUSION: For the first time, we demonstrate the behavior of plasma sphingolipids following transient cardiac ischaemia in humans. The observation supports the important role of sphingolipids level as a potential novel marker of transient or prolonged myocardial ischaemia.

SLE and pregnancy: the potential role for regulatory T cells.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that disproportionally affects women, especially in their reproductive years. SLE is associated with considerable pregnancy-related morbidity--including fetal loss, preterm birth, fetal growth restriction and pre-eclampsia. CD4+CD25+ regulatory T (T(REG)) cells have a potent immunosuppressive function and contribute to immunological self-tolerance. These cells might be essential for successful placental development by ensuring fetal tolerance. The numbers of T(REG) cells are augmented during normal pregnancy and, conversely, diminished numbers are associated with pregnancy loss and pre-eclampsia. Several studies have shown that patients with SLE have decreased numbers of T(REG) cells that might be functionally defective. This defective T(REG) cell functioning could predispose women with SLE to pregnancy complications. This article provides an overview of current knowledge of the role and function of T(REG) cells in SLE and pregnancy and how these cells might contribute to improving pregnancy-related outcomes in patients with SLE in the future.