Fibrosis is a fundamental component of the adverse structural remodeling of myocardium found in hypertensive heart disease (HHD). A replacement fibrosis appears at sites of previous cardiomyocyte necrosis to preserve the structural integrity of the myocardium. However, such scarring has adverse functional consequences. The extensive distribution of fibrosis involving the right and left heart suggests cardiomyocyte necrosis is widespread. Together, the loss of these contractile elements and fibrous tissue deposition in the form of stiff in-series and in-parallel elastic elements contributes to the progressive failure of this normally efficient muscular pump. Pathogenic mechanisms modulating fibrous tissue formation at sites of repair include auto-/ paracrine properties of locally generated angiotensin II and endothelin-1. Herein, we focus on the signal-transducer-effector pathway involved in cardiomyocyte necrosis and the crucial pathogenic role of intracellular Ca 2+ overloading, and subsequent induction of oxidative stress originating within its mitochondria that dictates the opening of the mitochondrial permeability transition pore. The ensuing osmotic destruction of these organelles is followed by necrotic cell death. It is now further recognized that Ca 2+ overloading of cardiac myocytes and mitochondria functioning as prooxidant is pathophysiologically counterbalanced by an intrinsically coupled Zn 2+ entry, which serves as antioxidant. The prospect of raising intracellular Zn 2+ by adjuvant nutriceutical supplementation can, therefore, be preferentially exploited to uncouple this intrinsically coupled Ca 2+ -Zn 2+ dyshomeostasis in favor of endogenous antioxidant defenses. Hence, novel cardioprotective strategies may be at hand and deserve to be further explored in the overall management of patients having HHD.
Inappropriately (relative to dietary Na + ) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na + have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca 2+ accumulation (EICA), or intracellular Ca 2+ overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca 2+ and Mg 2+ . In addition, we found intracellular Ca 2+ overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn 2+ , which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular-molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra-and intracellular Ca 2+ and Zn 2+ equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism.
Neurohormonal activation involving the hypothalamic-pituitary-adrenal axis and adrenergic nervous and renin-angiotensin-aldosterone systems is integral to stressor state-mediated homeostatic responses. The levels of effector hormones, depending upon the degree of stress, orchestrate the concordant appearance of hypokalemia, ionized hypocalcemia and hypomagnesemia, hypozincemia, and hyposelenemia. Seemingly contradictory to homeostatic responses wherein the constancy of extracellular fluid would be preserved, upregulation of cognate-binding proteins promotes coordinated translocation of cations to injured tissues, where they participate in wound healing. Associated catecholamine-mediated intracellular cation shifts regulate the equilibrium between pro-oxidants and antioxidant defenses, a critical determinant of cell survival. These acute and chronic stressor-induced iterations in extracellular and intracellular cations are collectively referred to as the cation crossroads. Intracellular cation shifts, particularly excessive accumulation of Ca2+, converge on mitochondria to induce oxidative stress and raise the opening potential of their inner membrane permeability transition pores (mPTPs). The ensuing loss of cationic homeostasis and adenosine triphosphate (ATP) production, together with osmotic swelling, leads to organellar degeneration and cellular necrosis. The overall impact of iterations in extracellular and intracellular cations and their influence on cardiac redox state, cardiomyocyte survival, and myocardial structure and function are addressed herein.
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