Stress Coping Strategies in the Heart: An Integrated View

Abstract

The heart is made up of an ordered amalgam of cardiac cell types that work together to coordinate four major processes, namely energy production, electrical conductance, mechanical work, and tissue remodeling. Over the last decade, a large body of information has been amassed regarding how different cardiac cell types respond to cellular stress that affect the functionality of their elaborate intracellular membrane networks, the cellular reticular network. In the context of the heart, the manifestations of stress coping strategies likely differ depending on the coping strategy outcomes of the different cardiac cell types, and thus may underlie the development of distinct cardiac disorders. It is not clear whether all cardiac cell types have similar sensitivity to cellular stress, how specific coping response strategies modify their unique roles, and how their metabolic status is communicated to other cells within the heart. Here we discuss our understanding of the roles of specialized cardiac cells that together make the heart function as an organ with the ability to pump blood continuously and follow a regular rhythm.

Selective enhancement of cardiomyocyte efficiency results in a pernicious heart condition

“…Importantly, this was prevented in cultured fibroblasts stretched in the presence of TUDCA. These findings provide support for the notion that coping strategy outcomes of the different cardiac cell types contribute to the complexity of cardiac disorders [1] as TUDCA treatment is effective in managing ER stress in fibroblasts to prevent fibrosis in Cardiac CRT+ hearts [17] but offered little therapeutic benefit to the other observed cardiac pathologies. Thus, a possible mechanism underlying the induction of heart pathology in Cardiac CRT+ mice, despite improved Cardiac CRT+ cardiomyocyte performance, is the unequal sensing of cellular stress and/or activation of stress coping strategies among the different cell types that make up the Cardiac CRT+ heart, leading to failure in the coordination of various cellular function at the organ level.…”

“…Calreticulin is the major ER Ca 2+ storage protein [29,30]. The protein is highly expressed in embryonic heart and despite this, the expression of calreticulin is sharply downregulated in adult cardiomyocytes [9] which rely on Ca 2+ to carry out its mechanical function in the heart [1]. In humans, studies have noted increased expression of calreticulin in the failing and hypertrophied hearts [11][12][13][14][15].…”

“…Notably, cardiac fibrogenesis was inhibited by TUDCA after selective induction of calreticulin overexpression in the murine cardiomyocytes in vivo [17]. The heart is comprised of multiple cell types that work together to carry out organ function [1]. Fibrogenesis is associated with activation of cardiac fibroblasts in response to Ex vivo analysis of the working heart with 30 min aerobic perfusion, 20 min ischemia, and 40 min aerobic reperfusion using the Langendorff perfusion system.…”

“…Ca 2+ -handling proteins associated with ER/ SR membrane are critical for muscle contraction and relaxation [32]. Just like other cells, cardiomyocytes have a network of perinuclear ER but they also possess the SR which represents a specialized form of the ER responsible for regulation of excitation-contraction coupling [1,8,33,34]. The SR plays a key role in maintaining cardiac excitation-contraction coupling and mechanical function of cardiomyocytes [8] while the ER is the driver of intracellular Ca2 +-dependent signal transduction and cellular Ca2+ homeostasis [8].…”

“…The heart is a multicellular organ that takes advantage of the functions of specialized cell types (cardiomyocytes, fibroblasts, macrophages, Purkinje and pacemaker, endothelial) to carry on mechanical work, tissue remodeling and energetics [ 1 ]. For example, cardiomyocytes are primarily responsible for the cardiac mechanical function and cardiac fibroblasts are involved in tissue remodeling [ 1 – 4 ]. Heart failure typically results from abnormally long periods of extreme mechanical activity [ 5 ] and cardiac remodeling induces fibrogenesis, initially an adaptive response, which leads to cardiac pathology.…”