Cardiac hypertrophy is an initial adaptive process in response to a variety of physiological and pathological stimuli. In certain conditions such as chronic hypertension, compensated hypertrophy an lead to congestive heart failure. Previous studies have proposed that abnormal excitation contraction coupling and regulation may be responsible for impaired contractility in failing heart. A number of Ca/2+ handling systems involved in myocardial contraction and the cellular basis for the defect in heart failure is not completely understood. In addition, the correlation between the functional abnormalities and the stages of hypertrophy, including before and during the onset of heart failure, as well as end stage congestive heart failure, has not been well- characterized. Our long term objective is to understand the cellular mechanisms that rigger cardiac hypertrophy and regulate the transition between compensated and decompensated phases of cardiac hypertrophy. This application focuses on cellular mechanisms important for myocardial Ca/2+ homeostasis . We hypothesize that changes in ionic currents and autonomic regulation that are involved in cellular Ca/2+ homeostasis occur in hypertrophied myocardium and that the degree of alteration is dependent upon the severity of hypertrophy and the presence of heart failure. To test this hypothesis, a transgenic mouse model of compensated hypertrophy which exhibits cardiac physiological events observed in animal models and human heart failure with a remarkable recapitulation with biochemical alterations associated with various stages of disease will be determined by patch clamp technique. Once the failure by transferring gene of certain defective components. This research is fundamental to our understanding of cellular mechanisms of cardiac hypertrophy and failure. These studies will not only field significant new information on the basic cellular mechanisms that regulate heart failure, but will also provide new and valuable insights into the design of drugs as well as novel therapeutic approaches for cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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University of Cincinnati
Schools of Medicine
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Yatani, A; Shen, Y-T; Yan, L et al. (2006) Down regulation of the L-type Ca2+ channel, GRK2, and phosphorylated phospholamban: protective mechanisms for the denervated failing heart. J Mol Cell Cardiol 40:619-28
Yatani, Atsuko; Xu, Da-Zhong; Irie, Keiichi et al. (2006) Dual effects of mesenteric lymph isolated from rats with burn injury on contractile function in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 290:H778-85
Yatani, Atsuko; Irie, Keiichi; Otani, Takayuki et al. (2005) RhoA GTPase regulates L-type Ca2+ currents in cardiac myocytes. Am J Physiol Heart Circ Physiol 288:H650-9
Yatani, Atsuko; Kim, Song-Jung; Kudej, Raymond K et al. (2004) Insights into cardioprotection obtained from study of cellular Ca2+ handling in myocardium of true hibernating mammals. Am J Physiol Heart Circ Physiol 286:H2219-28
Okumura, Satoshi; Takagi, Gen; Kawabe, Jun-ichi et al. (2003) Disruption of type 5 adenylyl cyclase gene preserves cardiac function against pressure overload. Proc Natl Acad Sci U S A 100:9986-90
Plank, David M; Yatani, Atsuko; Ritsu, Honda et al. (2003) Calcium dynamics in the failing heart: restoration by beta-adrenergic receptor blockade. Am J Physiol Heart Circ Physiol 285:H305-15
Li, Joan; Yatani, Atsuko; Kim, Song-Jung et al. (2003) Neurally-mediated increase in calcineurin activity regulates cardiac contractile function in absence of hypertrophy. Cardiovasc Res 59:649-57
Okumura, Satoshi; Kawabe, Jun-ichi; Yatani, Atsuko et al. (2003) Type 5 adenylyl cyclase disruption alters not only sympathetic but also parasympathetic and calcium-mediated cardiac regulation. Circ Res 93:364-71
Kim, Young-Kwon; Kim, Song-Jung; Yatani, Atsuko et al. (2003) Mechanism of enhanced cardiac function in mice with hypertrophy induced by overexpressed Akt. J Biol Chem 278:47622-8
Yatani, Atsuko; Xu, Da-Zhong; Kim, Song-Jung et al. (2003) Mesenteric lymph from rats with thermal injury prolongs the action potential and increases Ca2+ transient in rat ventricular myocytes. Shock 20:458-64

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