Highly specific interaction with foreign molecules is a unique feature of antibodies. Since 1975, when Keller and Milstein proposed the method of hybridoma technology and prepared mouse monoclonal...

Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) play a key role in the maintenance of the nervous tissue viability. IGF-1 and IGF-2 exhibit the neuroprotective effects by stimulating migration and proliferation of nervous cells, activating cellular metabolism, inducing regeneration of damaged cells, and regulating various stages of prenatal and postnatal development of the nervous system. The availability of IGFs for the cells is controlled via their interaction with the IGF-binding proteins (IGFBPs) that inhibit their activity. On the contrary, the cleavage of IGFBPs by specific proteases leads to the IGF release and activation of its cellular effects. The viability of neurons in the nervous tissue is controlled by a complex system of trophic factors secreted by auxiliary glial cells. The main source of IGF for the neurons are astrocytes. IGFs can accumulate as an extracellular free ligand near the neuronal membranes as a result of proteolytic degradation of IGFBPs by proteases secreted by astrocytes. This mechanism promotes interaction of IGFs with their genuine receptors and triggers intracellular signaling cascades. Therefore, the release of IGF by proteolytic cleavage of IGFBPs is an important mechanism of neuronal protection. This review summarizes the published data on the role of IGFs and IGFBPs as the key players in the neuroprotective regulation with a special focus on the specific proteolysis of IGFBPs as a mechanism for the regulation of IGF bioavailability and viability of neurons.

Cardiovascular diseases (CVD) are among the leading causes of death and disability worldwide. Pregnancy-associated plasma protein-A (PAPP-A) is a matrix metalloprotease localized on the cell surface. One of the substrates that PAPP-A cleaves is the insulin-like growth factor binding protein-4 (IGFBP-4), a member of the family of proteins that bind insulin-like growth factor (IGF). Proteolysis of IGFBP-4 by PAPP-A occurs at a specific site resulting in formation of two proteolytic fragments – N-terminal IGFBP-4 (NT-IGFBP-4) and C-terminal IGFBP-4 (CT-IGFBP-4), and leads to the release of IGF activating various cellular processes including migration, proliferation, and cell growth. Increased levels of the proteolytic IGFBP-4 fragments correlate with the development of CVD complications and increased risk of death in patients with the coronary heart disease, acute coronary syndrome, and heart failure. However, there is no direct evidence that PAPP-A specifically cleaves IGFBP-4 in the cardiac tissue under normal and pathological conditions. In the present study, using a primary culture of rat neonatal cardiomyocytes as a model, we have demonstrated that: 1) proteolysis of IGFBP-4 by PAPP-A occurs in the conditioned medium of cardiomyocytes, 2) PAPP-A-specific IGFBP-4 proteolysis is increased when cardiomyocytes are transformed to a hypertrophic state. Thus, it can be assumed that the enhancement of IGFBP-4 cleavage by PAPP-A and hypertrophic changes in cardiomyocytes accompanying CVD are interrelated, and PAPP-A appears to be one of the activators of the IGF-dependent processes in normal and hypertrophic-state cardiomyocytes.

One of the most vital processes of the body is the cardiovascular system’s proper operation. Physiological processes in the heart are regulated by the balance of cardioprotective and pathological mechanisms. The insulin-like growth factor system (IGF system, IGF signaling pathway) plays a pivotal role in regulating growth and development of various cells and tissues. In myocardium, the IGF system provides cardioprotective effects as well as participates in pathological processes. This review summarizes recent data on the role of IGF signaling in cardioprotection and pathogenesis of various cardiovascular diseases, as well as analyzes severity of these effects in various scenarios.

Hypertrophic changes in the ventricular myocardium accompany most cardiovascular diseases and represent a serious risk factor for sudden cardiac death. To date, a wide range of in vitro and in vivo models of hypertrophy have been developed; however, none of them allow for the simultaneous investigation of both biochemical and physiological aspects of its pathogenesis. This study proposes a method based on the induction of left ventricular hypertrophy (LVH) resulting from renovascular hypertension in rats, followed by the isolation of cardiomyocytes from their hearts. The study included 68 animals (32 1K1C type rats, 16 1K type rats, and 20 sham-operated (SO) rats). To induce LVH in the “one kidney one clip” (1K1C) rats, a clip was placed on the renal artery of the left kidney to restrict blood flow, after which the right kidney was removed. In the “one kidney” (1K) group, the right kidney was removed while the left kidney was remained intact, whereas in SO rats, the abdominal cavity was opened and then sutured without any manipulation of the kidneys. The latter two groups served as controls. After 1.5 months, the left ventricular mass in 1K1C rats exceeded that in both control groups by 1.2 times, while the arterial pressure in the 1K1C group increased by 1.4 times compared to both controls. Additionally, 1K1C rats exhibited a 1.4-fold increase in serum and urinary urea concentrations and a 1.5-fold enhancement in renal excretion, as assessed by creatinine clearance, compared to the control groups. The serum concentration of B-type natriuretic peptide (BNP) in 1K1C rats was twice as high as in the control groups. After LVH induction, primary cardiomyocyte cultures were derived from the hearts of control and hypertrophic rats. In the conditioned medium of the primary culture of ventricular cardiomyocytes from 1K1C rats, the BNP concentration was 3.4 times higher than in the control groups. Thus, it was demonstrated that cardiomyocytes isolated from 1K1C rats retain a hypertrophic phenotype, and this combined approach can be used to study cardiac hypertrophy in vivo and in vitro.