BNPs, Cardiac inflammation and Fibrosis

By Nadezhda Glezeva PhD

The early physiological processes predisposing the healthy heart to undergo changes towards an unstable, diseased state and eventually cardiac insufficiency are still under investigation. In the case of chronic HF, the disease continuum is commonly initiated following a chronic exposure of the CV system to high blood pressure.

Hypertension and High Blood Pressure

Hypertension (HTN) is the most common cause for LVDD and HFPEF and chronic exposure to high blood pressure gradually develops to first cause tissue inflammation and myocardial fibrosis, tissue ischaemia, intrinsic myocyte impairment, endothelial dysfunction, and apoptosis. This is followed by LVH, increased LV stiffness and inability of the ventricle to relax, reduced filling volume, and impaired diastolic dysfunction. The constellation of these abnormalities represents the phenotypic portrait of HHD.

Mounting evidence suggests that among all anomalies myocardial fibrosis and immune-inflammatory activation are most critically involved in the very early stages of HF, and BNP has been shown to regulate tightly both of these processes.

Brain Natriuretic Peptides and Cardiac Inflammation

Despite its role as a circulating endocrine factor implicated in the regulation of the blood pressure and volume systems, BNP also has potent autocrine / paracrine actions in the heart, which are implemented following its interaction with NPRA (natriuretic peptide receptor 1) and the subsequent production of cGMP.

NPRA deletion in mice (Npr1-/-) has been shown to cause salt-resistant hypertension, cardiac hypertrophy and fibrosis [1], while overexpression of the receptor caused arterial hypotension. Locally, targeted overexpression of NPRA in cardiomyocytes attenuated pressure-induced cardiac enlargement [2]. On the other hand, myocyte-specific NPRA deletion in mice caused cardiac hypertrophy and impaired diastolic relaxation. In the setting of deletion of the BNP gene (Nppb-/-), the knock-out animals developed focal cardiac ventricular fibrotic lesions and increased ventricular mRNA expression of pro-fibrotic genes including ACE, TGFβ3, and pro-α1-collagen [3]

Expression and function of BNP were more recently also shown in cardiac fibroblasts . Data from in vivo studies with human cardiac fibroblasts have supported an important paracrine role for the peptide in regulating fibroblast proliferation and function in cardiac hypertrophy via opposing the actions of TGFβ , by decreasing collagen synthesis and increasing MMP activity [4]. In in vivo studies, Npr1-/- mice had increased expression of fibrotic genes including MMP2, MMP9, TGFβ, TNFα, and total collagen.Taken together these studies establish BNP as a potential anti-fibrotic factor and a local regulator of ventricular remodelling in the heart.

The BNP/NPRA system

The BNP/NPRA system has recently also been shown to regulate and also be regulated by inflammatory networks in the diseased heart. Recent evidence from animal studies shows enhanced pro-inflammatory cytokine gene expression in Npr1-/- mice [5]. The group demonstrated three- to five-fold induction of TNFα, IL6, and TGFβ1 expression in the left ventricles of the knock-out animals. In another study, knock-out of NPRA in mice caused up-regulation of nuclear factor kappa B (NFκB) activity and TNFα expression supporting a role for BNP in counter-balancing these inflammatory mediators. In line with that, cardiac-specific overexpression of TNFα and IL6 in mice proved sufficient to induce cardiac hypertrophy and LVDD [6].

In vitro studies with neonatal rat ventricular cardiomyocytes have also reported increased synthesis and secretion of BNP following treatment of the cells with TNFα or IL1β [7]. The group also reported increased plasma BNP levels in the absence of hemodynamic changes in an in vivo mouse model of sepsis and supported a unique regulatory role for BNP (but not ANP) in the setting of an inflammatory process. Summarizing all of the above, it seems very likely that the BNP/NPRA/cGMP system has an important anti-inflammatory role in the heart.

BNP levels and Inflammation

Recent data has shown substantial correlation between BNP levels and serum markers of inflammation. BNP and IL6 mRNA levels were consistently elevated in cardiac hypertrophy complicated with diastolic heart dysfunction in spontaneously hypertensive rats, indicating active inflammatory processes in these hearts [8]. Additionally, significant correlation between IL6, BNP and LV end-diastolic dimension (LVEDD) values was found in patients with idiopathic LV dysfunction. Elevated BNP correlated with TNF and LVEDD parameters in chronic HF patients [163]. Ahmad et al. also identified an association between TNFα, IL6, NT-proBNP and LV function recovery of patients with dilated cardiomyopathy [9]. In addition, NTproBNP levels correlated with C-reactive protein values and systolic and diastolic blood pressure in chronic renal failure patients with or without known cardiomyopathy .

A significant correlation between central BNP levels and levels of TNFα, IL6 and IL8 in hypertensive patients at risk of developing HFPEF (not published). Furthermore, peripheral BNP levels were found to correlate with central levels of TNFα, IL6, IL8, and MCP1.

Release of Inflammatory Mediators in high BNP cardiac Patients

It is so far not known what promotes the release of inflammatory mediators in high-BNP cardiac patients. It is however considered that BNP could be able to modulate the inflammatory response by affecting different immune cell functions, like leukocyte migration, and activation, or by interfering with the integrity of the vasculature, i.e. the endothelial and smooth muscle layers.

In fact, a recently published study from Chiurchiu et al. showed that BNP can upregulate the production of pro- and anti-inflammatory molecules like reactive oxygen- and nitrogen species, leukotriene B4, and prostaglandin E2; increase IL10 levels; and affect cell motility of THP1 monocytic cells [10]. In a separate study, co-culture of peripheral blood mononuclear cells (PBMC) from cardiac transplant recipients with BNP caused a reduction in pro-inflammatory cytokines (TNFα, IL6, IL1α), while expression of anti-inflammatory and regulatory cytokines (IL4, IL5, IL13) was preserved.

While all these data are relatively new, when taken together, they suggest that there exists a circumstantial relationship between BNP and inflammatory cytokines, an area/concept which has not been thoroughly explored in the context of heart disease.
As this work aimed to specifically assess the role of BNP in cardiovascular inflammation, in order to make conclusions for BNP’s role in the heart, it is of essential importance to study in more detail issues such as BNP processing, release and functionality in healthy subjects and heart disease patients; BNP/NPRA signalling; the effects of BNP on leukocyte activity and functions; and the relation of BNP to cardiac inflammatory processes in control subjects, in asymptomatic or minimally-symptomatic HTN patients, in LVDD patients, and HFPEF patients.


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