Atrophic Cardiomyocyte Signaling in Hypertensive Heart Disease

Abstract

Cardinal pathologic features of hypertensive heart disease (HHD) include not only hypertrophied cardiomyocytes and foci of scattered microscopic scarring, a footprint of prior necrosis, but also small myocytes ensnared by fibrillar collagen where disuse atrophy with protein degradation would be predicted. Whether atrophic signaling is concordant with the appearance of HHD and involves oxidative and endoplasmic reticulum (ER) stress remains unexplored. Herein, we examine these possibilities focusing on the left ventricle (LV) and cardiomyocytes harvested from hypertensive rats receiving 4 wks aldosterone/salt treatment (ALDOST) alone or together with ZnSO4, a nonvasoactive antioxidant, with the potential to attenuate atrophy and optimize hypertrophy. Compared to untreated age-/sex-/strain-matched controls, ALDOST was accompanied by: a) LV hypertrophy with preserved systolic function; b) concordant cardiomyocyte atrophy (<1000 μm2) found at sites bordering on fibrosis where they were re-expressing β-myosin heavy chain; and c) upregulation of ubiquitin ligases, MuRF1 and atrogin-1, and elevated 8-isoprostane and unfolded protein ER response with mRNA upregulation of stress markers. ZnSO4 cotreatment reduced lipid peroxidation, fibrosis and the number of atrophic myocytes, together with a further increase in cell area and width of atrophied and hypertrophied myocytes, and improved systolic function, but did not attenuate elevated blood pressure. We conclude that atrophic signaling, concordant with hypertrophy, occurs in the presence of a reparative fibrosis and induction of oxidative and ER stress at sites of scarring where myocytes are atrophied. ZnSO4 cotreatment in HHD with ALDOST attenuates the number of atrophic myocytes, optimizes size of atrophied and hypertrophied myocytes, and improves systolic function.

Small Dedifferentiated Cardiomyocytes Bordering on Microdomains of Fibrosis

“…They have dedifferentiated, re-expressing fetal genes that include β-myosin heavy chain (β-MHC) (3-7). Sequestered and dedifferentiated cardiomyocytes are small (<1000 μm 2 ) (6, 8) comparable in size to atrophic cells seen with hemodynamic unloading that accompanies heterotopic transplantation, banding the thoracic segment of the inferior vena cava, or a period of mechanical circulatory support (9-11). Other interventions which reduce ventricular work to invoke cardiac atrophy include prolonged bed rest and weightlessness of zero gravity (12).…”

“…Generalized cardiomyocyte atrophy also accompanies dietary caloric restriction (13) or taurine deficiency (14), dexamethasone treatment (15), sympathetic neuron ablation (16), or cachexia of malignancy (17). Localized cardiomyocyte atrophy, on the other hand, is observed at sites where fibrillar collagen normally envelops myocytes (e.g., insertion of mitral valve leaflets or emergence of chordae tendineae from papillary muscle) (4-6), or at sites of fibrosis commonly present with pressure overload (4, 5), hypertensive heart disease (6, 18-21) or following myocarditis (22). Myocytes ensnared by stiff fibrils of collagen have an imposed workload reduction and, therefore, predisposition to disuse atrophy (6, 23).…”

“…Localized cardiomyocyte atrophy, on the other hand, is observed at sites where fibrillar collagen normally envelops myocytes (e.g., insertion of mitral valve leaflets or emergence of chordae tendineae from papillary muscle) (4-6), or at sites of fibrosis commonly present with pressure overload (4, 5), hypertensive heart disease (6, 18-21) or following myocarditis (22). Myocytes ensnared by stiff fibrils of collagen have an imposed workload reduction and, therefore, predisposition to disuse atrophy (6, 23). Foci of scarring, which are widely scattered throughout the failing heart (24), and with attendant atrophy of neighboring myocytes inevitably contribute to diastolic and systolic ventricular dysfunction, respectively.…”

“…Toward this end, we examined the hypertensive heart disease that accompanies 4 wks aldosterone/salt treatment (ALDOST), where a mitochondriocentric prooxidant pathway to myocyte necrosis with ensuing reparative fibrosis, or scarring, and perivascular fibrosis of intramural coronary vasculopathy create the substrate for myocyte sequestration, activated myoFb and where oxidative stress emanating from subsarcolemmal mitochondria is operative (6, 8, 34-37). To rescue the dedifferentiated myocyte phenotype, the 4-wk ALDOST regimen was discontinued and a 4-wk period of neurohormonal withdrawal was combined with a pharmacoregenerative strategy aimed at accelerating the restoration of redox equilibrium.…”

“…To rescue the dedifferentiated myocyte phenotype, the 4-wk ALDOST regimen was discontinued and a 4-wk period of neurohormonal withdrawal was combined with a pharmacoregenerative strategy aimed at accelerating the restoration of redox equilibrium. Termed assisted recovery , it included: i ) an oral Ca 2+ , Mg 2+ and Zn 2+ supplement for 4 days to restore their serum levels which had declined in response to marked urinary and fecal excretory losses, and consequent ionized hypocalcemia accounting for secondary hyperparathyroidism with parathyroid hormone-mediated myocyte and mitochondrial Ca 2+ overloading and attendant oxidative stress (38, 39); ii ) 4 wks of oral ZnSO 4 to enhance endogenous Zn 2+ -based antioxidant defenses that aided in the recovery of atrophic myocytes (6, 40); and iii ) 4 wks oral nebivolol, a β 1 adrenergic receptor antagonist with additional properties as a β 3 receptor agonist which, in turn, promotes nitric oxide (NO) generation and consequent NO-based release of inactive Zn 2+ bound to metallothionein-1 and where increased cytosolic free [Zn 2+ ] i further raises these defenses (41, 42). …”