Disturbances in Calcium Metabolism and Cardiomyocyte Necrosis: The Role of Calcitropic Hormones

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Abstract

A synchronized dyshomeostasis of extra- and intracellular Ca2+, expressed as plasma ionized hypocalcemia and excessive intracellular Ca2+ accumulation, respectively, represents a common pathophysiologic scenario that accompanies several diverse disorders. These include low-renin and salt-sensitive hypertension, primary aldosteronism and hyperparathyroidism, congestive heart failure, acute and chronic hyperadrenergic stressor states, high dietary Na+, and low dietary Ca2+ with hypovitaminosis D. Homeostatic responses are invoked to restore normal extracellular [Ca2+]o, including increased plasma levels of parathyroid hormone and 1,25(OH)2D3. However, in cardiomyocytes these calcitropic hormones concurrently promote cytosolic free [Ca2+]i and mitochondrial [Ca2+]m overloading. The latter sets into motion organellar-based oxidative stress, in which the rate of reactive oxygen species generation overwhelms their detoxification by endogenous antioxidant defenses, including those related to intrinsically coupled increments in intracellular Zn2+. In turn, the opening potential of the mitochondrial permeability transition pore increases, allowing for osmotic swelling and ensuing organellar degeneration. Collectively, these pathophysiologic events represent the major components to a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis. From necrotic cells, there follows a spillage of intracellular contents, including troponins, and a subsequent wound healing response with reparative fibrosis or scarring. Taken together, the loss of terminally differentiated cardiomyocytes from this postmitotic organ and the ensuing replacement fibrosis each contribute to the adverse structural remodeling of myocardium and progressive nature of heart failure. In conclusion, hormone-induced ionized hypocalcemia and intracellular Ca2+ overloading comprise a pathophysiologic cascade common to diverse disorders and that initiates a mitochondriocentric pathway to nonischemic cardiomyocyte necrosis.

Introduction

Despite disparate etiologic origins, several disorders share a common downstream pathophysiologic cascade revolving around a dyshomeostasis of extra- and intracellular Ca2+. Expressed as ionized hypocalcemia and excessive intracellular Ca2+ accumulation (EICA), respectively, this scenario naturally involves calcitropic hormones: the catecholamines, parathyroid hormone (PTH), and 1,25(OH)2D3, a steroid molecule also known as calcitriol or vitamin D. These disorders include low-renin and salt-sensitive hypertension, primary aldosteronism and hyperparathyroidism, congestive heart failure (CHF), acute and chronic hyperadrenergic states, high dietary Na+, and reduced dietary Ca2+ with hypovitaminosis D.

Plasma ionized hypocalcemia represents a relative deficiency of extracellular [Ca2+]o. It can manifest in response to (1) heightened fecal and/or urinary excretory Ca2+ losses in the presence of fixed dietary Ca2+ intake, (2) catecholamine-mediated translocation of plasma Ca2+ into tissues, and (3) reduced dietary Ca2+, often in association with vitamin D deficiency. Homeostatic responses, invoked by ionized hypocalcemia, seek to restore extracellular [Ca2+]o. They include the increased secretion of PTH by the parathyroid glands to promote the release of Ca2+ stored in bone and PTH-driven renal formation of 1,25(OH)2D3, which enhances Ca2+ absorption from the gastrointestinal tract and Ca2+ reabsorption by the kidneys.

In cardiomyocytes, these calcitropic hormones, however, simultaneously promote L-type Ca2+ channel activity, leading to increased cytosolic free [Ca2+]i and, in turn, mitochondrial [Ca2+]m overloading with organellar-based oxidative stress. The rate of reactive oxygen species generation overwhelms their rate of neutralization by endogenous antioxidant defenses, including closely coupled increments in intracellular Zn2+. Excessive intracellular Ca2+ accumulation in the presence of fallen [Ca2+]o levels has prompted Fujita and Palmieri1 to implicate a scenario of a Ca2+ paradox. At the subcellular level, and considered a response intended to maintain intracellular Ca2+ homeostasis, mitochondrial [Ca2+]m rises, targeting the subsarcolemmal population of cardiac mitochondria in particular.2, 3, 4 This sets into motion a mitochondriocentric signal-transducer-effector (MSTE) pathway to cardiomyocyte necrosis with subsequent spillage of cellular contents (eg, troponins). These contents represent “danger signals” that stimulate the immune system accounting for the invasion of inflammatory cells as well as phenotypically transformed fibroblast-like cells or myofibroblasts to the site of injury. Necrosis is, therefore, referred to as “dirty” cell death, evoking a wound-healing response that eventuates in a reparative fibrosis.5, 6 Microscopic scars are indeed morphological footprints of necrosis. This contrasts to programmed cell death, where apoptotic cardiomyocytes are rapidly scavenged by macrophages without subsequent tissue repair or fibrosis to represent “sterile” cell death.

Microscopic scars are scattered throughout the myocardium of the right and left sides of the heart in both ischemic and dilated (idiopathic) cardiomyopathies and hypertensive heart disease.7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Elevations in plasma troponins, a biochemical marker of cardiomyocyte necrosis, are present at the time of hospitalization for decompensated heart failure or poorly controlled hypertension and are predictive of worsened outcomes and poor prognosis.17, 18, 19, 20, 21, 22, 23, 24, 25, 26 Elevated troponins are also seen, with each admission implicating cardiomyocyte necrosis to be an ongoing event. In what is arguably a postmitotic organ unable to withstand such losses given the fixed population of these highly differentiated and specialized cells, necrosis and fibrosis likely contribute to the progressive nature of heart failure.

The purpose of this review is several fold: (1) to highlight the pathophysiologic events pivoting around the dyshomeostasis of Ca2+ metabolism, the role of calcitropic hormones, and the MSTE pathway to cardiomyocyte necrosis and (2) to emphasize the metabolism of intrinsically coupled Zn2+, an antioxidant, and its cardioprotective potential. We begin with a relevant historical perspective.

Section snippets

Historical perspective

Many of the disorders noted earlier have their origins rooted in inappropriate neurohormonal activation that includes the hypothalamic-pituitary-adrenal axis, the adrenergic nervous (ANS), and renin-angiotensin-aldosterone (RAAS) systems and whose effector hormones can prove toxic to cardiomyocytes.27, 28, 29 Fleckenstein et al,30 now 50 years ago, hypothesized that the hyperadrenergic state, which accompanies acute stressors, would lead to catecholamine-mediated EICA and dysfunction of

Disturbances in calcium metabolism leading to plasma ionized hypocalcemia

An activation of the ANS and RAAS accompanies acute and chronic stressor states. Effector hormones represented, respectively, by elevated circulating levels of the catecholamines and aldosterone each lead to plasma ionized hypocalcemia, albeit via different pathophysiologic cascades (see Fig 1).

In the case of an acute hyperadrenergic state, such as that accompanies bodily injury (eg, subarachnoid hemorrhage, acute myocardial infarction, burns, or traumatic injury), reductions in plasma ionized

Lost intracellular Ca2+ homeostasis

Ca2+ is an essential intracellular messenger, especially in contractile cells, such as cardiomyocytes. However, an excessive accumulation of Ca2+, which Rasmussen et al75 referred to as Ca2+ intoxication, becomes a cellular toxin. Normally, EICA is minimized by intracellular autoregulatory responses, wherein the rate of Ca2+ influx is limited by specific and specialized L-type Ca2+ channels of an otherwise impermeable sarcolemma membrane and that is in equilibrium with the rate of Ca2+ efflux.

Mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis

The adverse consequences of elevated plasma epinephrine levels on cardiomyocyte survival that appear with acute bodily injury (eg, subarachnoid hemorrhage) or adrenal medullary tumor (pheochromocytoma) have been well described.29,32, 33, 34, 35 The role of catecholamine excess that accompanies marked emotional stress can putatively account for ballooning (akinesia) of the left ventricular (LV) apex, also termed Takotsubo cardiomyopathy.76 Isoproterenol has been used to address the cytotoxicity

Clinical correlates of calcium dyshomeostasis with cardiomyocyte necrosis

A dyshomeostasis of divalent cations is found in patients hospitalized with decompensated biventricular failure having a dilated cardiomyopathy of ischemic or nonischemic origins and in low-renin and salt-sensitive hypertension.46, 47, 48,70 This aberrant cation-hormone profile is also present in patients with primary aldosteronism.50, 51, 85, 86 Elevated PTH serves as a stimulus to adrenal aldosterone production and contemporaneous elevations in plasma aldosterone. In patients with primary

A dyshomeostasis of zinc as antioxidant

The importance of a deficiency in antioxidant reserves is also contributory to the imbalance in pro-oxidant:antioxidant equilibrium leading to cardiomyocyte necrosis that accompanies neurohormonal activation.126, 127, 128 Zinc is integral to antioxidant defenses as well as wound healing.129 An increased expression of metallothionein, a Zn2+-binding protein, occurs at sites of tissue injury, including the heart where it promotes local accumulation of Zn2+ and its involvement in gene

Overall summary and conclusions

Acute and chronic stressor states are accompanied by neurohormonal activation that includes the ANS and RAAS. An ensuing hyperadrenergic state, coupled with SHPT via ionized hypocalcemia, provokes cardiomyocyte Ca2+ overloading, including [Ca2+]m of the subsarcolemmal population of mitochondria with induction of oxidative stress and opening of their inner membrane mPTP. These events represent the major components of an MSTE pathway to organellar degeneration and, ultimately, cardiomyocyte

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

Acknowledgments

This work was supported, in part, by NIH grants R01-HL73043 and R01-HL90867 (KTW). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Authors have no conflicts of interest to disclose.

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