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Aleksey Zima, PhD

Professor
Calcium signaling, Ion channels and pumps, Oxidative stress

Education

  • MS, Biophysics, Kiev State University; Ukraine
  • PhD, Biophysics, Bogomoletz Institute of Physiology; Kiev, Ukraine

Research Interests

Cardiovascular biology, intracellular calcium regulation, ion channel biophysics

Heart function vitally relies on precisely controlled intracellular calcium regulation during each cardiac cycle. In single cardiomyocytes, the majority of calcium is released from the sarcoplasmic reticulum (SR) as a result of activation of a special calcium release channel - the ryanodine receptor (RyR). Mechanisms controlling RyR function represent critical sites at which contractility and intracellular calcium homeostasis can be modulated. Abnormal RyR activity can generate life-threatening arrhythmias and has been implicated in heart failure. Thus, it makes the RyR a clinically important site for potential therapeutic intervention. The main goal of our research is to define the mechanisms that regulate SR calcium release in the normal and failing heart.



Beta-Adrenergic receptor (beta-AR) stimulation initiates a signaling cascade that produces the physiologically important positive inotropic‌ effect. This effect is mainly mediated via protein kinase (PKA and Ca/CaMKII) phosphorylation of important calcium transport systems, including the RyR. However, the contribution of RyR phosphorylation to positive inotropy remains highly controversial. Thus, the one aim of our research is to determine the contribution of RyR phosphorylation to the positive inotropic effect during beta-AR stimulation.

Beta-AR stimulation also induces an arrhythmogenic‌ action by increasing the likelihood of spontaneous calcium waves during diastole. The underlying mechanism here is also unclear. While RyRs are known to be subject of redox regulation and beta-AR stimulation results in elevated reactive oxygen species production, the role of these free radicals in the generation of arrhythmogenic calcium waves has not been systematically explored to date. Thus, the second aim of our research is to determine the role of reactive oxygen species in the generation of arrhythmogenic calcium waves during beta-AR stimulation.

In a future, we are planning to extend these studies in a model of failing heart. Particularly, how alteration of RyR sensitivity to calcium contributes to generation of calcium-dependent arrhythmias during heart failure. What is the functional role of protein kinase activation and reactive oxygen species production in dysregulation of RyR function in heart failure?

Primary Techniques
• Measurements of contractile and electrical (ECG) activity of the whole-heart
• Enzymatic isolation of ventricular myocytes from rabbit, mouse and rat heart
• Measurements of dynamic of intracellular calcium using high-speed laser scanning confocal microscopy and fluorescent indicators in living cells
• Measurements of reactive oxygen species production, mitochondrial calcium concentration and mitochondrial membrane potential with confocal microscopy
• Measurements of single ryanodine receptor activity reconstructed into lipid bilayers
• Measurements of phosphorylation level and free thiol content of ryanodine receptors
• Adenoviral gene transfer strategies to manipulate the expression level of important proteins involved in intracellular calcium regulation

Publications/Research Listings

  • Bovo E, Lipsius SL and Zima AV - Reactive Oxygen Species Contribute to Generation of Arrhythmogenic Ca2+ Waves during -Adrenergic Receptor Activation in Rabbit Cardiomyocytes. 2012 J Physiol (in press)
  • Bovo E, Mazurek SR, Blatter L.A and Zima AV - Regulation of Sarcoplasmic Reticulum Ca2+ leak by Cytosolic Ca2+ in Rabbit Ventricular Myocytes. J Physiol. 2011 15, 589: 6039-50
  • Picht E, Zima AV, Shannon TR, Duncan AM, Blatter AM, Bers DM Dynamic Calcium Movement inside Cardiac Sarcoplasmic Reticulum during Release Circ Res 2011; 108: 847-856
  • Zima AV, Bovo E, Bers DM and Blatter LA - Ca2+ Spark Dependent and Independent Sarcoplasmic Reticulum Ca2+ Leak in Normal and Failing Rabbit Ventricular Myocytes J Physiol. 2010; 588: 4743-57 
  • Domeier TL, Blatter LA and Zima AV - Alteration of sarcoplasmic reticulum Ca2+ release termination by ryanodine receptor sensitization and in heart failure J Physiol. 2009; 587: 5197-5209  
  • Zima AV, Picht E, Bers DM, Blatter LA - Termination of Cardiac Ca2+ Sparks: Role of Intra-SR [Ca2+], Release Flux, and Intra-SR Ca2+ Diffusion. Circ Res. 2008;103(8):e105-15     
  • Other Publications