Deficiency of Cardiac Natriuretic Peptide Signaling Promotes Peripartum Cardiomyopathy-Like Remodeling in the Mouse Heart

Abstract

Background: The maternal circulatory system and hormone balance both change dynamically during pregnancy, delivery, and the postpartum period. Although atrial natriuretic peptides and brain natriuretic peptides produced in the heart control circulatory homeostasis through their common receptor, NPR1, the physiologic and pathophysiologic roles of endogenous atrial natriuretic peptide/brain natriuretic peptide in the perinatal period are not fully understood. Methods: To clarify the physiologic and pathophysiologic roles of the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system during the perinatal period, the phenotype of female wild-type and conventional or tissue-specific Npr1-knockout mice during the perinatal period was examined, especially focusing on maternal heart weight, blood pressure, and cardiac function. Results: In wild-type mice, lactation but not pregnancy induced reversible cardiac hypertrophy accompanied by increases in fetal cardiac gene mRNAs and ERK1/2 (extracellular signaling-regulated kinase) phosphorylation. Npr1-knockout mice exhibited significantly higher plasma aldosterone level than did wild-type mice, severe cardiac hypertrophy accompanied by fibrosis, and left ventricular dysfunction in the lactation period. Npr1-knockout mice showed a high mortality rate over consecutive pregnancy–lactation cycles. In the hearts of Npr1-knockout mice during or after the lactation period, an increase in interleukin-6 mRNA expression, phosphorylation of signal transducer and activator of transcription 3, and activation of the calcineurin–nuclear factor of the activated T cells pathway were observed. Pharmacologic inhibition of the mineralocorticoid receptor or neuron-specific deletion of the mineralocorticoid receptor gene significantly ameliorated cardiac hypertrophy in lactating Npr1-knockout mice. Anti–interleukin-6 receptor antibody administration tended to reduce cardiac hypertrophy in lactating Npr1-knockout mice. Conclusions: These results suggest that the characteristics of lactation-induced cardiac hypertrophy in wild-type mice are different from exercise-induced cardiac hypertrophy, and that the endogenous atrial natriuretic peptide/brain natriuretic peptide–NPR1 system plays an important role in protecting the maternal heart from interleukin-6–induced inflammation and remodeling in the lactation period, a condition mimicking peripartum cardiomyopathy.

Endothelial Natriuretic Peptide Receptor 1 Play Crucial Role for Acute and Chronic Blood Pressure Regulation by Atrial Natriuretic Peptide

“…EC- Npr1 -KO and endothelial cell–specific Npr1 –overexpressing mice (EC- Npr1 -Tg) were developed. 13,14…”

“…EC-Npr1-KO and endothelial cell-specific Npr1-overexpressing mice (EC-Npr1-Tg) were developed. 13,14 Preparation of ANP-Conjugated Quantum Dots…”

Guanylyl cyclase‐A phosphorylation decreases cardiac hypertrophy and improves systolic function in male, but not female, mice

“…Moreover, physiologic cardiac hypertrophy associated with lactation was exaggerated in GC-A −/− mice and correlated with increased cardiac ERK1/2 phosphorylation and activity. 69 Conversely, in GC-A −/− mice, exaggeration of pathologic hypertrophy post-TAC was not dependent on ERK1/2 activity. 9,11 Finally, the ability of ANP to block phenylephrine-dependent increases in neonatal rat CM CSA was shown to require increased, not decreased, ERK1/2 activity, which differs from our model.…”

“…Why aldosterone was unchanged in the original GC-A −/− mice 5 and increased in the same mice many years later is not known. 69 A previous study reported that mice with increasing numbers of GC-A alleles have proportionally increased GC-A activity, proportionally increased blood testosterone levels, and proportionally decreased blood pressure. 56 Hence, it was suggested that the GC-A dependent increases in testosterone levels contribute to the hypotension observed in mice with increased GC-A activity.…”

Inhibition of cardiac PERK signaling promotes peripartum cardiac dysfunction

“…Bromocriptine (BCR) does not ameliorate cardiac function during l the postpartum term in CM-KO mice. Previous studies have shown that anti-PRL agents, such as BCR, a dopamine D2 receptor agonist, not only improved cardiac function by reducing the plasma 16 K PRL levels 2 but also suppressed cardiac hypertrophy by suppressing the plasma aldosterone and 23 K PRL levels during the lactation term 16 . We examined the effect of BCR in two consecutive deliveries in CTRL or CM-KO mice.…”