The Dysfunction of Ca2+ Channels in Hereditary and Chronic Human Heart Diseases and Experimental Animal Models.

Chronic heart diseases, such as coronary heart disease, heart failure, secondary arterial hypertension, and dilated and hypertrophic cardiomyopathies, are widespread and have a fairly high incidence of mortality and disability. Most of these diseases are characterized by cardiac arrhythmias, conduction, and contractility disorders. Additionally, interruption of the electrical activity of the heart, the appearance of extensive ectopic foci, and heart failure are all symptoms of a number of severe hereditary diseases. The molecular mechanisms leading to the development of heart diseases are associated with impaired permeability and excitability of cell membranes and are mainly caused by the dysfunction of cardiac Ca2+ channels. Over the past 50 years, more than 100 varieties of ion channels have been found in the cardiovascular cells. The relationship between the activity of these channels and cardiac pathology, as well as the general cellular biological function, has been intensively studied on several cell types and experimental animal models in vivo and in situ. In this review, I discuss the origin of genetic Ca2+ channelopathies of L- and T-type voltage-gated calcium channels in humans and the role of the non-genetic dysfunctions of Ca2+ channels of various types: L-, R-, and T-type voltage-gated calcium channels, RyR2, including Ca2+ permeable nonselective cation hyperpolarization-activated cyclic nucleotide-gated (HCN), and transient receptor potential (TRP) channels, in the development of cardiac pathology in humans, as well as various aspects of promising experimental studies of the dysfunctions of these channels performed on animal models or in vitro.

Mitochondrial mechanisms by which gasotransmitters (H2S, NO and CO) protect cardiovascular system against hypoxia.

Over past few years, there has been a dramatic increase in studying physiological mechanisms of the activity of various signaling low-molecular molecules that directly or indirectly initiate adaptive changes in the cardiovascular system cells (CVSC) to hypoxia. These molecules include biologically active endogenous gases or gasotransmitters (H2S, NO and CO) that influence on many cellular processes, including mitochondrial biogenesis, oxidative phosphorylation, K+/Ca2+ exchange, contractility of cardiomyocytes (CM) and vascular smooth muscle cells (VSMC) under conditions of oxygen deficiency. The present review focuses on the mechanistic role of the gasotransmitters (NO, H2S, CO) in cardioprotection. The structural components of these mechanisms involve mitochondrial enzyme complexes and redox signal proteins, K+ and Ca2+ channels, and mitochondrial permeability transition pore (MPTP) that have been considered as the final molecular targets of mechanisms underlying antioxidant and mild mitochondrial uncoupling effects, preconditioning, vasodilatation and adaptation to hypoxia. In this article, we have reviewed recent findings on the gasotransmitters and proposed a unifying model of mitochondrial mechanisms of cardioprotection.

Signaling mechanisms of apoptosis-like programmed cell death in unicellular eukaryotes.

In unicellular eukaryotes, apoptosis-like cell death occurs during development, aging and reproduction, and can be induced by environmental stresses and exposure to toxic agents. The essence of the apoptotic machinery in unicellular organisms is similar to that in mammals, but the apoptotic signal network is less complex and of more ancient origin. The review summarizes current data about key apoptotic proteins and mechanisms of the transduction of apoptotic signals by caspase-like proteases and mitochondrial apoptogenic proteins in unicellular eukaryotes. The roles of receptor-dependent and receptor-independent caspase cascades are reviewed.

cAMP-dependent signal pathways in unicellular eukaryotes.

The review summarizes current data about mechanisms of signal transduction with participation of cAMP (cyclic adenosine monophosphate) and elements of the complex cAMP-protein kinase A (PKA) signal pathway in unicellular eukaryotes. Conceptions of evolutionary origin of eukaryotic signal transduction systems are developed.

Phosphoinositide signaling in unicellular eukaryotes.

The review considers the up to date achievements in the role of membrane phosphoinositides and keys enzymes of the lipid branch of the phosphoinositide signal pathway (PI-pathway) in unicellular eukaryotes. Particular attention is paid to mechanisms of phospholipase C (PLC) activation and the PLC interaction both with cell surface receptors and with the effector cytoplasm targets. The role of protein kinase C (PKC) in intracellular signaling and the relationship of the PI-pathway key enzymes with protein tyrosine kinases (PTK)-signaling and cAMP-protein kinase A (PKA) pathway are discussed.