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IGFBP-4 Proteolysis by PAPP-A in a Primary Culture of Rat Neonatal Cardiomyocytes under Normal and Hypertrophic Conditions

Daria V. Serebryanaya1,a*, Daria A. Adasheva1, Alexey A. Konev2, Marina M. Artemieva3, Ivan A. Katrukha1,2, Alexander B. Postnikov1,2, Natalia A. Medvedeva3, and Alexey G. Katrukha1,2

1Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

2HyTest Ltd., Turku, Finland, 20520

3Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

* To whom correspondence should be addressed.

Received August 6, 2021; Revised September 3, 2021; Accepted September 3, 2021
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.
KEY WORDS: cardiovascular diseases, heart failure, cardiomyocytes, primary culture, proteolysis, PAPP-A, IGFBP-4, hypertrophy, endothelin-1

DOI: 10.1134/S0006297921110043