Eplerenone enhances cardioprotective effects of standard heart failure therapy through matricellular proteins in hypertensive heart failure

Abstract

In a hypertensive heart failure rat model, the addition of eplerenone to conventional heart failure therapy further improves cardiac structural and functional parameters, delaying the progression of heart failure. These beneficial effects of eplerenone were associated with normalization of matricellular protein expression.

Early Spironolactone Treatment Attenuates Heart Failure Development by Improving Myocardial Function and Reducing Fibrosis in Spontaneously Hypertensive Rats

“…We have not identified any studies in literature evaluating the effects of early spironolactone treatment alone in SHR during the transition from compensated hypertrophy to decompensated heart failure. Munoz-Pacheco et al [24] treated two-month old SHR with eplerenone plus conventional heart failure therapy for 20 months and observed structural and functional cardiac improvement, delayed heart failure progression, and matricellular protein expression normalization. As previously reported, aldosterone can induce several deleterious effects on the cardiovascular system.…”

“…It presents early arterial hypertension and left ventricular hypertrophy which evolves slowly to ventricular dysfunction and heart failure during maturity and senescence [3,22,23]. The transition from long-term compensated left ventricular hypertrophy to cardiac failure is characterized by marked myocardial fibrosis with an increase in collagen type I and collagen type I-to-III ratio [2,24,25,26,27]. The potential beneficial role of aldosterone blockers in preventing or attenuating pressure overload-induced cardiac remodeling and heart failure development has not yet been completely clarified.…”

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension

“…95 Aldosterone also increases levels of the profibrotic connective tissue growth factor, collagen, and the matrix remodeling proteins matrix metalloproteinase-2 and matrix metalloproteinase -9 in cultured human pulmonary artery endothelial cells. 96 Similarly, in other experimental models, aldosterone has been implicated in increased synthesis and deposition of the extracellular matrix proteins collagen I and III, fibronectin, and matrix metalloproteinases-3, -7, 12, -13 as well as the matricellular proteins thrombospondin 1, osteonectin, periostin, and tenascin C. 97 In turn, these changes are associated with fibrillar collagen deposition in pulmonary arterioles and frank RV replacement fibrosis in PAH in vivo. 9, 80, 90 Aldosterone may also exert these pathogenic effects on cardiopulmonary tissue through alternative fibrotic signaling pathways linked to mineralocorticoid receptor activation, including reactive oxygen species generation, NF-κB signaling, and other pro-inflammatory pathways.…”

Matricellular Proteins and Organ Fibrosis

“…Cardiac overexpression of CCN5 or antibody targeting of Postn preserved cardiac function and decreased myocardial fibrosis (5,37). Interestingly, normalization of matricellular protein expression by aldosterone receptor antagonism, further improved cardiac structure and function in addition to standard pharmacological heart failure therapy (98). In liver disease patients increased serum OPN levels correlated with the degree of fibrosis, while OPN neutralization in mice protected from liver fibrosis progression (58, 61).…”