Mitochondria-targeted Cardioprotection in Aldosteronism

Abstract

Chronic aldosterone/salt treatment (ALDOST) is accompanied by an adverse structural remodeling of myocardium that includes multiple foci of microscopic scarring representing morphologic footprints of cardiomyocyte necrosis. Our previous studies suggested that signaltransducer-effector pathway leading to necrotic cell death during ALDOST includes intramitochondrial Ca 2+ overloading, together with an induction of oxidative stress and opening of the mitochondrial permeability transition pore (mPTP). To further validate this concept, we hypothesized mitochondria-targeted interventions will prove cardioprotective. Accordingly, 8-wkold male Sprague-Dawley rats receiving 4 wks ALDOST were cotreated with either quercetin (Q), a flavonoid with mitochondrial antioxidant properties, or cyclosporine A (CsA), an mPTP inhibitor, and compared to ALDOST alone or untreated, age-/sex-matched controls. We monitored: mitochondrial free Ca 2+ and biomarkers of oxidative stress, including 8-isoprostane and H 2 O 2 production; mPTP opening; total Ca 2+ in cardiac tissue; collagen volume fraction (CVF) to quantify replacement fibrosis, a biomarker of cardiomyocyte necrosis; and employed TUNEL assay to address apoptosis in coronal sections of ventricular myocardium. Compared to controls, at 4 wks ALDOST we found: a marked increase in mitochondrial H 2 O 2 production and 8-isoprostane levels, an increased propensity for mPTP opening, and greater concentrations of mitochondrial free [Ca 2+ ] m and total tissue Ca 2+ , coupled with a 5-fold rise in CVF without any TUNEL-based evidence of cardiomyocyte apoptosis. Each of these pathophysiologic responses to ALDOST were prevented by Q or CsA cotreatment. Thus, mitochondria play a central role in initiating the cellular-molecular pathway that leads to necrotic cell death and myocardial scarring. This destructive cycle can be interrupted and myocardium salvaged with its structure preserved by mitochondria-targeted cardioprotective strategies.

Myofibroblast secretome and its auto-/paracrine signaling

“…This includes the use of targeted antioxidants or inhibition of the opening of the mitochondrial inner membrane permeability transition pore which is less resistant in these organelles as contrasted to interfibrillar mitochondria [64-66]. Such strategies have included nutriceuticals (flavonoids) [67], pharmaceuticals (cyclosporine A or third-generation β-adrenergic-receptor antagonists) [68], inhaled hydrogen gas [69], or microRNAs [70-72]. …”

Phosphoproteome mapping of cardiomyocyte mitochondria in a rat model of heart failure

“…In particular complexes I and III of ETC are major sites of reactive oxygen species generation as a by-product of normal metabolism. As we have shown in our ALDOST model, the pathophysiological scenario leading to cardiomyocyte necrosis includes aberrant production of reactive oxygen species and increased oxidative stress that eventually overwhelms protective antioxidant scavengers with ensuing opening of the mPTP pore to result in cell death [1, 5]. Our pilot results include characterization of two phosphorylation sites in cytochrome b c-1 complex subunit 6 (complex III subunit 6) and of one site in ATP synthase subunit alpha.…”

“…We have used a rat model of aldosterone/salt treatment (ALDOST) to simulate the neurohormonal profile of human CHF and to interrogate the pathophysiologic link between RAAS activation and nonischemic, hormone-mediated cardiomyocyte necrosis [3]. A mitochondriocentric signal-transducer-effector pathway (MSTE) was identified involving the subsarcolemmal (SSM) population of mitochondria [1, 5]. Its features include: calcitropic hormone-driven calcium overloading; their induction of oxidative stress and loss of ATP synthesis; and opening of the inner membrane permeability transition pore (mPTP) to allow osmotic swelling and organellar degeneration with ensuing cell death.…”

“…Its features include: calcitropic hormone-driven calcium overloading; their induction of oxidative stress and loss of ATP synthesis; and opening of the inner membrane permeability transition pore (mPTP) to allow osmotic swelling and organellar degeneration with ensuing cell death. Cotreatment with mitochondria-targeted interventions, either an antioxidant or mPTP opening inhibitor, have proven cardioprotective [5, 6]. …”

Reverse remodeling and recovery from cachexia in rats with aldosteronism

“…In cardiomyocytes harvested at 4-wk ALDOST, we found intracellular Ca 2ϩ overloading, which included both cytosolic free [Ca 2ϩ ] i and SSM mitochondrial free [Ca 2ϩ ] m domains. The latter was coupled to the induction of oxidative stress in cardiac tissue (17,34) and these organelles, as evidenced by their significantly increased production of H 2 O 2 , and opening potential for their mPTP. This pathophysiologic sequence to nonischemic cardiomyocyte necrosis is embodied by a mitochondriocentric signal-transducer-effector pathway occurring in SSM and interventions targeting specific pathway components have proven cardioprotective (6,34).…”