Background-Phosphoinositide 3-kinase (PI3K) p110␣ plays a key role in insulin action and tumorigenesis. Myocyte contraction is initiated by an inward Ca 2ϩ current (I Ca,L ) through the voltage-dependent L-type Ca 2ϩ channel (LTCC). The aim of this study was to evaluate whether p110␣ also controls cardiac contractility by regulating the LTCC. Methods and Results-Genetic ablation of p110␣ (also known as Pik3ca), but not p110␤ (also known as Pik3cb), in cardiac myocytes of adult mice reduced I Ca,L and blocked insulin signaling in the heart. p110␣-null myocytes had a reduced number of LTCCs on the cell surface and a contractile defect that decreased cardiac function in vivo. Similarly, pharmacological inhibition of p110␣ decreased I Ca,L and contractility in canine myocytes. Inhibition of p110␤ did not reduce I Ca,L . Conclusions-PI3K p110␣ but not p110␤ regulates the LTCC in cardiac myocytes. Decreased signaling to p110␣ reduces the number of LTCCs on the cell surface and thus attenuates I Ca,L and contractility. (Circulation. 2009;120:318-325.)Key Words: calcium Ⅲ ion channels Ⅲ signal transduction Ⅲ myocytes Ⅲ contractility T he force generated by a heartbeat results from the coordinated contraction of individual myocytes and is regulated by changes in the intracellular Ca 2ϩ concentration. Each contraction-relaxation cycle is initiated by cell membrane depolarization elicited by action potentials, resulting in a small inward Ca 2ϩ current through the L-type Ca 2ϩ channel (LTCC) located on the cell surface. This inward Ca 2ϩ current (I Ca,L ) triggers a larger release of Ca 2ϩ from the sarcoplasmic reticulum, resulting in myocyte contraction. Thus I Ca,L is an important determinant of contractile force. Clinical Perspective on p 325Studies suggest that class I phosphoinositide (PI) 3-kinases (PI3Ks) modulate I Ca,L in cardiac myocytes. [1][2][3] These enzymes phosphorylate PI 4,5-bisphosphate (PI [4,5]P 2 ) to generate PI 3,4,4,5]P 3 ) in vivo. Cardiac myocytes contain at least 2 class IA PI3Ks, p110␣ and ␤, and class IB p110␥. Recent evidence indicates that both class IA PI3K isoforms play a role in tumorigenesis. 4,5 Indeed, upregulated PI3K signaling is seen in many human malignancies, and a number of PI3K inhibitors are currently being tested in clinical trials. 5,6 However, rodent models of diabetes and other models in which PI3K signaling is compromised in the heart suggest that this pathway is needed to maintain normal LTCC function in cardiac myocytes. 1,2,[7][8][9] The PI3K isoform that maintains normal I Ca,L in the heart has not been identified. Here we show that ablation of p110␣ in the heart of adult mice and pharmacological inhibition of p110␣ in isolated canine ventricular myocytes leads to a decrease in I Ca,L and contractility defects. Ablation of p110␤ or inhibition of this isoform did not reduce I Ca,L . Our results suggest the potential for adverse effects on cardiac contractility with cancer therapies that target p110␣ but not p110␤. In addition, inhibition of p110␣ may provide an explana...

OBJECTIVE-Contraction of cardiac myocytes is initiated byCa 2ϩ entry through the voltage-dependent L-type Ca 2ϩ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling. RESEARCH DESIGN AND METHODS-We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2 Akita mutation versus nondiabetic littermates.RESULTS-Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased L-type Ca 2ϩ current (I Ca,L ) density in myocytes compared with control nondiabetic littermates. The lower I Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P 3 stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P 3 infusion eliminated only the difference in voltage dependence of steady-state inactivation of I Ca,L .CONCLUSIONS-Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca 2ϩ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility. Diabetes 56:2780-2789, 2007 C ardiac complications are an important cause of morbidity and mortality in type 1 diabetic patients. This is partly due to the presence of hypertension and coronary artery disease, which are commonly associated with diabetes. Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2-5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force. However, the molecular mechanism that underlies the LTCC defect in diabetic myocytes is unclear.Class I phosphatidylinositol (PI) 3-kinases preferentially phosphorylate PI 4,5-bisphosphate [PI(4,5)P 2 ] to form phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] in vivo and exhibit substantial activation in response to stimulation with insulin or other hormones. Studies in neuron...

Magnesium alloys may potentially be applied as biodegradable metallic materials in cardiovascular stent. However, the high corrosion rate hinders its clinical application. In this study, a new approach was adopted to control the corrosion rate by fabricating a biocompatible micro-arc oxidation/poly-L-lactic acid (MAO/PLLA) composite coating on the magnesium alloy WE42 substrate and the biocompatibility of the modified samples was investigated. The scanning electronic microscope (SEM) images were used to demonstrate the morphology of the samples before and after being submerged in hanks solution for 4 weeks. The degradation was evaluated through the magnesium ions release rate and electrochemical impedance spectroscopy (EIS) test. The biocompatibility of the samples was demonstrated by coagulation time and hemolysis behavior. The result shows that the poly-L-lactic acid (PLLA) effectively improved the corrosion resistance by sealing the microcracks and microholes on the surface of the MAO coating. The modified samples had good compatibility.

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