Cardiac natriuretic peptide deficiency sensitizes the heart to stress-induced ventricular arrhythmias via impaired CREB signalling

Abstract

Aims The cardiac natriuretic peptides (atrial natriuretic peptide [ANP] and B-type natriuretic peptide [BNP]) are important regulators of cardiovascular physiology, with reduced natriuretic peptide (NP) activity linked to multiple human cardiovascular diseases. We hypothesized that deficiency of either ANP or BNP would lead to similar changes in left ventricular structure and function given their shared receptor affinities. Methods and Results We directly compared murine models deficient of ANP or BNP in the same genetic backgrounds (C57BL6/J) and environments. We evaluated control, ANP deficient (Nppa-/-) or BNP deficient (Nppb-/-) mice under unstressed conditions and multiple forms of pathological myocardial stress. Survival, myocardial structure, function and electrophysiology, tissue histology, and biochemical analyses were evaluated in the groups. In vitro validation of our findings was performed using human derived induced pluripotent stem cell cardiomyocytes (iPS-CM). In the unstressed state, both ANP and BNP deficient mice displayed mild ventricular hypertrophy which did not increase up to 1 year of life. NP-deficient mice exposed to acute myocardial stress secondary to thoracic aortic constriction (TAC) had similar pathological myocardial remodeling but a significant increase in sudden death. We discovered that the NP-deficient mice are more susceptible to stress induced ventricular arrhythmias using both in vivo and ex vivo models. Mechanistically, deficiency of either ANP or BNP led to reduced myocardial cGMP levels and reduced phosphorylation of the cAMP response element-binding protein (CREBS133) transcriptional regulator. Selective CREB inhibition sensitized wild type hearts to stress induced ventricular arrhythmias. ANP and BNP regulate cardiomyocyte CREBS133 phosphorylation through a cGMP-dependent protein kinase 1 (PKG1) and p38 mitogen activated protein kinase (p38 MAPK) signaling cascade. Conclusions Our data show that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK and CREB activity. Cardiac natriuretic peptide deficiency leads to a reduction in CREB signaling which sensitizes the heart to stress induced ventricular arrhythmias. Translational Perspective Our study found that ANP or BNP deficiency leads to increased sudden death and ventricular arrhythmias after acute myocardial stress in murine models. We discovered that ANP and BNP act in a non-redundant fashion to maintain myocardial cGMP levels and uncovered a unique role for these peptides in regulating cardiomyocyte p38 MAPK and CREB signaling through a cGMP-PKG1 pathway. Importantly, this signaling pathway was conserved in human cardiomyocytes. This study provides mechanistic insight into how modulating natriuretic peptide levels in human heart failure patients reduces sudden death and mortality.

Maternal Undernutrition Induces Cell Signalling and Metabolic Dysfunction in Undifferentiated Mouse Embryonic Stem Cells

“…2A ). We also included Nppb which encodes brain natriuretic peptide within the MAPK effectors since the hormone mediates the MAPK pathway to regulate cardiac response to stress [ 30 ]. Thus, LPD ESC lines exhibited upregulation of Nppb in RNA sequencing ( P < 0.0001) and confirmed by qRT-PCR (Fig.…”

“…Further, LPD lines were downregulated in Ddx17 which encodes multitasking RNA helicases that similarly modulate cellular activity from apoptosis to proliferation [ 48 ]. Lastly, LPD lines exhibited upregulation of Nppb encoding B-type natriuretic peptide (BNP) which contributes to MAPK-mediated stress response in cardiomyocytes [ 30 ]. BNP plays a role in cardiac development and elevated plasma levels associate with heart failure and myocardial infarction [ 49 ].…”

The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

“…In light of strong evidence in experimental animals of protean beneficial actions of ANP/BNP across many tissues affecting the integrity of the cardiovascular system [ 2 , 39 ] and the deleterious impact of ablating ANP/BNP pathway activity [ 40 , 41 ], it is unsurprising that circulating concentrations of ANP/BNP products within the normal range have beneficial effects in maintaining cardiovascular and metabolic health in healthy people [ 42 , 43 ]. Whether these subtle differences in plasma concentrations predict subsequent cardiovascular health is the crucial question addressed in this prospective study.…”

“…Acquired factors such as obesity—lowering BNP [ 19 ]—also need consideration and will be assessed by changes in BMI. Although both ANP and BNP activate the same receptor (NPR1), their variable expression, location, and metabolism highlight the need to measure both bioactive forms in plasma [ 41 ] in associative studies linking levels with changing indicators of vascular, metabolic, and cardiac function in the 15 years after middle age when the incidence of heart disease increases greatly. No other study has examined these relationships in healthy participants.…”

EPHB2 knockdown mitigated MI-induced myocardial injury by inhibiting MAPK signaling

“…These ndings based on genetic diseases also suggest that the MAPK pathway is closely related to heart function and development. Another study found that ANP and BNP maintain myocardial cGMP levels to regulate cardiomyocyte p38 MAPK activity, sensitizing the heart to stress induced ventricular arrhythmias [40]. Recent studies have shown that KLF15 overexpression can reduce cardiomyocyte apoptosis and improve cardiac dysfunction in MI mice partly by inhibiting the p38 /MAPK signaling pathway [41].…”