Integrins in cardiac hypertrophy: lessons learned from culture systems

Abstract

Heart growth and pathological changes are accompanied by extracellular matrix-dependent alterations in integrins and integrin-associated proteins, suggesting their role in heart development and disease. Most of our knowledge on the involvement of integrins in heart pathology is provided by the in vivo experiments, including cardiac hypertrophy models. However, in vivo studies are limited by the complex organization of heart tissue and fail to discern cell types and particular integrins implicated in hypertrophic signalling. This problem is being addressed by isolated cardiomyocyte primary cultures, which have been successfully used in different in vitro disease models. This review aimed to analyse the general approaches to studying integrins and integrin-associated signalling pathways in cardiac hypertrophy focusing on the in vitro systems. The lessons learned from culture experiments on the models of hypertrophy induced by stretch, stimulating factors, and/or extracellular matrix components are summarized, demonstrating the major involvement of integrin-mediated signalling in cardiac hypertrophic response and its apparent crosstalk with signal pathways induced by stretch or hypertrophy stimulating factors. The benefits and perspectives of using cardiomyocyte primary culture as a hypertrophy model are discussed.

Piezo1 is the cardiac mechanosensor that initiates the cardiomyocyte hypertrophic response to pressure overload in adult mice

“…First, Piezo1 can be activated by increased membrane tension 32,33 , which might reasonably be expected due to increased membrane forces associated with pressure overload. Force could also be transduced to the Piezo1 channel via cytoskeletal tethers or crosstalk with proteins that link the cardiomyocyte to the extracellular matrix, such as integrins, many of which have been implicated in the development of cardiac hypertrophy [46][47][48] . Our studies of ventricular myocytes from multiple organisms suggest localization of both Piezo1 and TRPM4 to the T-tubular system 19 .…”

Cardiomyocyte-fibroblast crosstalk in the postnatal heart

“…The ECM represents a major regulator of intercellular processes in cardiac cells, in addition to providing integrity and mechanical support, responsible for functional and phenotypic changes ( Bildyug, 2021 ). After birth, the heart undergoes extensive alterations in the ECM composition and structure to adapt to physiological requirements of the growing body.…”

“…Major works on integrins role are mostly focused on development and disease using in vitro models. In cardiomyocytes, the main integrins are α 1 β 1 , α 5 β 1 , and α 7 β 1 , which are receptors for mainly collagen, fibronectin, and laminin, and these integrins are dynamically regulated during development ( Bildyug, 2021 ). For example, cardiomyocyte integrins β 1D and β 1A are co-expressed in heart of E11 embryos, but the expression of β 1A declines as β 1D increases until it becomes the only β 1 isoform present in cardiomyocytes a few days after birth ( Brancaccio et al, 1998 ; Meagher et al, 2021 ).…”

“…Cellular crosstalk is active in the postnatal period, when cardiomyocytes undergo cell cycle arrest simultaneously with a two-fold increase in the number of cardiac fibroblasts ( Anversa et al, 1980 ; Pinto et al, 2016 ). Along with the increase in number of cardiac fibroblasts, the ECM undergoes remodeling with synthesis and reorganization of the matrix to be able to withstand the forces that are generated postnatally in the ventricles ( Bildyug, 2021 ). Neonatal cardiomyocytes can adhere to ECM components of either the basement membrane or the interstitial matrix and these connections influence their development ( Bowers et al, 2010 ).…”

Roles of focal adhesion proteins in skeleton and diseases

“…Thus, FAs have an essential position in regulation of the biological behaviors of cells and play a key role in human health and disease. A large number of studies have revealed the important role of FAs in the initiation and progression of cancers, such as prostate cancer, breast cancer, hepatocellular carcinoma, and glioblastoma 9 , hematologic disorders 10 , kidney diseases 11 , neurodegenerative diseases 12 , cardiovascular diseases 13 , digestive system diseases 14 and metabolic diseases 15 . Recently, increasing evidence reports that FA proteins can regulate the biological behaviors of cells, and participate in the damage and repair of tissues in skeletal system 16 , 17 , 18 .…”