Pharmacological Therapy in the Heart as an Alternative to Cellular Therapy: A Place for the Brain Natriuretic Peptide?

Abstract

The discovery that stem cells isolated from different organs have the ability to differentiate into mature beating cardiomyocytes has fostered considerable interest in developing cellular regenerative therapies to treat cardiac diseases associated with the loss of viable myocardium. Clinical studies evaluating the potential of stem cells (from heart, blood, bone marrow, skeletal muscle, and fat) to regenerate the myocardium and improve its functional status indicated that although the method appeared generally safe, its overall efficacy has remained modest. Several issues raised by these studies were notably related to the nature and number of injected cells, as well as the route and timing of their administration, to cite only a few. Besides the direct administration of cardiac precursor cells, a distinct approach to cardiac regeneration could be based upon the stimulation of the heart's natural ability to regenerate, using pharmacological approaches. Indeed, differentiation and/or proliferation of cardiac precursor cells is controlled by various endogenous mediators, such as growth factors and cytokines, which could thus be used as pharmacological agents to promote regeneration. To illustrate such approach, we present recent results showing that the exogenous administration of the natriuretic peptide BNP triggers “endogenous” cardiac regeneration, following experimental myocardial infarction.

Left Ventricular Remodelling: A Problem in Search of Solutions

“…showed a continued benefit at 3 years of follow-up, 77 with an 82 % decrease in cardiovascular events. However, results of the CUPID2 phase II trial (n=343) 78 its pharmacological boosting is a novel concept.…”

Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+epicardium-derived cells

“…BNP binding to the receptors NPR-A and NPR-B, but not NPR-C, increases intracellular cyclic guanosine 3′,5′-monophosphate (cGMP) levels. cGMP modulates the protein kinase G activity and induces phosphorylation at Ser16 of phospholamban (PLB) 17 . Increased intracellular cGMP levels simultaneously activate GMP-related cation channels, leading to cGMP extrusion from the cytoplasm into the circulation.…”

“…BNP is a cardiac hormone belonging to the natriuretic peptide family along with atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP). It is mainly secreted in the ventricles by cardiomyocytes, fibroblasts, and endothelial and precursor cells 16,17 . BNP binds to guanylyl cyclase receptors, NPR-A and NPR-B, thus increasing the intracellular cGMP level 18 .…”

“…BNP secreted by cardiac cells acts on different organs such as the kidneys (modulating sodium and water excretion), vessels (increasing dilation), fat (increasing lipolysis), and pancreas (modulating insulin secretion) 17,22 . In the heart, the role of BNP remains unclear, although a majority of cardiac cells (cardiomyocytes, fibroblasts, endothelial cells) express BNP receptors in physiological and pathological states 16 .…”

“…Furthermore, in clinic, a treatment (LCZ696 or Entresto, Novartis) based on inhibition of neprilysin, an enzyme involved in the degradation of the natriuretic peptides, leads to reduced rate of mortality in patients suffering from heart failure with reduced and preserved cardiac contractility or ejection fraction 25 . Although BNP treatment inhibits fibrosis and protects cardiomyocytes from cell death, the cellular mechanisms responsible for this cardioprotective effect have not been fully elucidated 16,17,24 . Curiously, we observed that BNP stimulates in vitro and in vivo (i.e., in adult infarcted hearts) the proliferation of cardiac nonmyocyte cells (NMCs) expressing the stem cell antigen-1 (Sca-1) 26 .…”