The Aging Heart, Myocardial Fibrosis, and its Relationship to Circulating C-Type Natriuretic Peptide

Abstract

Myocardial aging is characterized by LV fibrosis leading to diastolic and systolic dysfunction. Studies have established the potent anti-fibrotic and anti-proliferative properties of C-type natriuretic peptide (CNP), however the relationship between circulating CNP, LV fibrosis and associated changes in LV function with natural aging are undefined. Accordingly, we characterized the relationship of plasma CNP with LV fibrosis and function in 2, 11 and 20 month old male Fischer rats. Further in vitro, we establish the anti-proliferative actions of CNP and the participation of the clearance receptor using adult human cardiac fibroblasts. Here we establish for the first time that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in LV fibrosis which precedes impairment of diastolic and systolic function. Additionally we demonstrate in cultured adult human cardiac fibroblasts that the direct anti-proliferative actions of high dose CNP may involve a non-cGMP pathway via the clearance receptor. Taken together these studies provide new insights into myocardial aging and the relationship to the anti-fibrotic and anti-proliferative peptide CNP.

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…The cGMP‐dependent signaling appears to be central for antifibrotic effects of CNP 88, 90. Evidence from Burnett's laboratory suggests that a non‐cGMP‐dependent pathway also mediates the antifibrotic effects of CNP 78. In conclusion, antifibrotic and ‐hypertrophic effects of CNP appear to be mediated both by activation of NPRB and by a non‐cGMP‐dependent mechanism, whereas blood‐pressure–lowering effect of CNP is not dependent on activation of NPRB.…”

“…However, plasma levels of CNP are very low even in patients with severe HF. Levels of circulating CNP actually appear to decrease in rats during aging, and this correlates with an increase in cardiac fibrosis 78. In addition to the heart, head and neck tissue are important sources of CNP 79…”

Urinary C-type natriuretic peptide excretion: a potential novel biomarker for renal fibrosis during aging

“…We recently demonstrated that a progressive decline in circulating CNP characterizes natural aging and is strongly associated with a reciprocal increase in cardiac fibrosis which preceded cardiac dysfunction (29). Although CNP lacks natriuretic and diuretic activity, CNP may have important renal-protective properties which serve to maintain renal structure and function, such as inhibition of glomerular fibrosis after renal injury (4).…”

“…We also hypothesized that age-related increases in urinary CNP precedes an elevation in proteinuria. To address these hypotheses, we assessed circulating and urinary CNP in a Fischer rat model of experimental aging, which is equivalent to human aging from adolescence to the six decade of life (29), and also determined renal structural and functional adaptations to the aging process. Finally, we investigated the presence and localization of CNP by immunohistochemistry in the kidneys of young and old, healthy human kidney donors.…”

Mitochondria and the Aging Heart

“…[41] The increased wall thickness is accompanied by decreased cardiomyocyte count and increased left ventricular collagen content, which are features of fibrosis. [42] Animal studies have demonstrated left ventricular collagen content increases linearly with age but can increase two-fold during the later years of life. [42] Overall, the cumulative impact of decreased cardiomyocyte count, increased collagen deposition and increased stiffness leads to significant ventricular dysfunction which is a major characteristic of the aging heart.…”