whereas, Akt/PKB overexpression in transgenic mice results in car diac hypertrophy, increased amplitude of Ca2 transients and enhanced L type membrane Ca2 currents. Lipopolysaccharide treatment of rats also leads to arrhyth mogenesis attributable to reduced mRNA levels encoding for L type Ca2 subunits. We reported that LPS dir ectly reduces Ca2 transients in HL 1 cells. however, LPS has no direct effect on L type Ca2 currents in these cells, acting instead to reduce the funny current, If, as also shown by others. Thus, to whatever extent sepsis reduces cardiomyocyte i and Ca2 transients by in hibition of PI3K/Akt PKB, elevated cytokines most likely effect these reductions and not LPS directly.
On the other hand, the present findings suggest that the amelioration of sepsis and endotoxemia by preconditioning or ische mia may result from upregulation of the PK3/Akt PKB signaling pathways, which directly increases i available for excitation contraction coupling in cardiomyocytes. All PI3K/Akt PKB inhibitors used in these experiments inhibited Ca2 transients and significantly decreased i. however, we cannot attribute the importance of one inhibitor over and against that of the others. Similar inhibition Ca2 transients and i by LY294002 at either 20 or 1 uM rules out toxicity by the drug. Still, there is considerable variability among HL 1 cells regarding the cells under these conditions. Indeed, we have been able to elicit robust Ca2 transients in otherwise quiescent cells by perfusing the cells with an inhibitor of the delayed rectifier K channels . which are prevalent in HL 1 cells.
Thus, variation among HL 1 cells in the strength of repolarizing K current during action potentials or in cells at rest may account for the different rates and amplitudes of Ca2 transients as well as i Conclusions In sum, we have found that inhibitors of the PI3K/Akt sig naling cascade decrease total i, intracellular Ca2 transients and membrane ICa in a murine, immorta lized cardiomyocyte cell line, HL 1 cells. These data dem onstrate that PI3K/Akt dependent signaling is required for normal Ca2 metabolism in murine cardiomyocytes. This extends our knowledge of the role of PI3K/Akt signaling in cardiovascular homeostasis. We conclude that maintaining myocardial PI3K/Akt signaling is essential for cardiomyo cyte function in the presence and absence of disease.
Background Bronchial asthma is a chronic inflammatory disorder of the airways, with episodic occurrences of airflow obstruction, and hypersensitivity and hyperresponsive ness to various stimuli. Asthma is one of the most com mon diseases, occurring in approximately 300 million people of all ages and ethnic backgrounds Cilengitide worldwide. Many attempts have been made over decades to discover the etiology of the disease, and thousands of papers have been published.