Cellular and molecular pathways to myocardial necrosis and replacement fibrosis

Abstract

Fibrosis is a fundamental component of the adverse structural remodeling of myocardium present in the failing heart. Replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium, but not without adverse functional consequences. The extensive nature of this microscopic scarring suggests cardiomyocyte necrosis is widespread and the loss of these contractile elements, combined with fibrous tissue deposition in the form of a stiff in-series and in-parallel elastic elements, contributes to the progressive failure of this normally efficient muscular pump. Cellular and molecular studies into the signal-transducer-effector pathway involved in cardiomyocyte necrosis have identified the crucial pathogenic role of intracellular Ca2+ overloading and subsequent induction of oxidative stress, predominantly confined within its mitochondria, to be followed by the opening of the mitochondrial permeability transition pore that leads to the destruction of these organelles and cells. It is now further recognized that Ca2+ overloading of cardiac myocytes and mitochondria serves as a prooxidant and which is counterbalanced by an intrinsically coupled Zn2+ entry serving as antioxidant. The prospect of raising antioxidant defenses by increasing intracellular Zn2+ with adjuvant nutriceuticals can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca2+ - Zn2+ dyshomeostasis. Hence, novel yet simple cardioprotective strategies may be at hand that deserve to be further explored.

Fig. 1

The appearance of secondary hyperparathyroidism (SHPT) during aldosterone/salt treatment (ALDOST) is associated with increased excretory losses of Ca²⁺ and Mg²⁺, and the consequent appearance of plasma-ionized hypocalcemia and hypomagnesemia. Elevations in parathyroid hormone (PTH) seek to restore extracellular homeostasis of these divalent cations through their resorption from bone, absorption from gut, and reabsorption by kidney promoted by the steroid hormone 1,25(OH)₂D₃. Paradoxically, PTH elaboration is responsible for intracellular Ca²⁺ overloading and the induction of oxi-/nitrosative stress, which leads to cardiomyocyte necrosis and consequent replacement fibrosis, or scarring. Adapted from Alsafwah et al. [115]

Fig. 2

Our current understanding of the pathways involving intrinsically coupled dyshomeostasis of Ca²⁺ and Zn²⁺ found in ALDOST. Increased excretory losses of these divalent cations lead to hypocalcemia and hypozincemia. Consequent secondary hyperparathyroidism with persistent elevations in circulating parathyroid hormone (PTH) are accompanied by uncontrolled Ca²⁺ entry via L-type Ca²⁺ channels (LTCC) to saturate intracellular binding and storage sites, and ultimately to intracellular [Ca²⁺]_i overloading and excessive Ca²⁺ sequestration within mitochondria. An induction of oxidative stress and generation of reactive oxygen species (ROS) ensue involving mitochondria. The rise in [Zn²⁺]_i and [Zn²⁺]_m involves increased Zn²⁺ entry via LTCC to a minor extent, while the majority of [Zn²⁺]_i is regulated by membrane-bound Zn transporters, including importers and exporters, Zip1 and ZnT-1, respectively, and its binding to metallothionein (MT)-1 to minimize cytotoxicity. Reprinted from Kamalov et al. [66]