The Importance of Natriuretic Peptides in Cardiometabolic Diseases.

The natriuretic peptide (NP) system is composed of 3 distinct peptides (atrial natriuretic peptide or ANP, B-type natriuretic peptide or BNP, and C-type natriuretic peptide or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor). ANP and BNP function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload on the heart. Although the role of NPs in cardiovascular homeostasis has been extensively studied and well established, much remains uncertain about the signaling pathways in pathological states like heart failure, a state of impaired natriuretic peptide function. Elevated levels of ANP and BNP in heart failure correlate with disease severity and have a prognostic value. Synthetic ANP and BNP have been studied for their therapeutic role in hypertension and heart failure, and promising trials are under way. In recent years, the expression of ANP and BNP in human adipocytes has come to light. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism. NPR-A signaling in skeletal muscles and adipocytes is emerging as pivotal to the maintenance of long-term insulin sensitivity, which is disrupted in obesity and reduced glucose-tolerance states. Genetic variants in the genes encoding for ANP and BNP have been associated with a favorable cardiometabolic profile. In this review, we discuss several pathways that have been proposed to explain the role of NPs as endocrine networkers. There is much to be explored about the therapeutic role of NPs in improving metabolic milieu. © Endocrine Society 2020.

An endocrine axis between the heart and the kidneys was first established by the discovery of atrial natriuretic peptide (ANP) by Adolfo J. de Bold in 1981 [1]. The role of natriuretic peptides (NPs) in cardiovascular homeostasis has been extensively studied and well established, although much remains uncertain about the impaired natriuretic peptide signaling pathways in pathological states like heart failure. In recent years, the expression of ANP and B-type natriuretic peptide (BNP) in human adipocytes has come to light [2]. Through their role in promotion of adipocyte browning, lipolysis, lipid oxidation, and modulation of adipokine secretion, they have emerged as key regulators of energy consumption and metabolism [3]. This highlights the role of the heart as a potential endocrine “networker” for energy expenditure, which could have tremendous therapeutic implications in the management of metabolic disorders like diabetes mellitus (DM) and obesity.

1. Physiology

The natriuretic peptide system is composed of 3 distinct peptides (ANP, BNP, and C-type NP or CNP) and 3 receptors (natriuretic peptide receptor-A or NPR-A or particulate guanynyl cyclase-A [GC-A], natriuretic peptide receptor-B or NPR-B or particulate guanynyl cyclase-B, and natriuretic peptide receptor-C or NPR-C or clearance receptor) [4].

A. Natriuretic Peptides

In humans, ANP is a 28-amino acid peptide and BNP is a 32-amino acid peptide. ANP is predominantly secreted from the heart as a cardiac hormone in response to atrial stretch. BNP has 2 dominant molecular forms: proBNP-108 and BNP-32. BNP-32 is dominant in the atrial tissue, whereas proBNP-108 is dominant in the ventricular tissue [5]. ProBNP-108 is cleaved into BNP-32 and NT-proBNP-76 as it is secreted. ANP levels increase in response to elevated atrial pressures, whereas BNP is a reflection of ventricular overload [4].

Mechanical stretch and stress of atrial and ventricular walls are potent inducers of ANP and BNP, respectively. In addition, animal model studies have suggested that myocardial ischemia and hypoxia also stimulate ANP and BNP secretion independent of myocardial stretch [6]. Several humoral factors, including angiotensin II, endothelin-1, thyroid hormones, glucocorticoids and sex steroids, inflammatory cytokines like interleukin-1 and -6, and tumor necrosis factor-α, have also been shown to modulate ANP and BNP secretion [2].

The physiological role of CNP in vascular and heart tissues has garnered significant attention in recent years. It is detected in low levels widely in the central nervous system, endothelium, kidney, bone, and heart [7]. CNP is translated as a 126-amino acid prepropeptide and processed, likely via enzyme furin, into NT-proCNP, CNP-53, and CNP-22. CNP-22 is rapidly degraded and is reported to have a very short half-life of 2.6 minutes in humans. CNP-53 is the most biologically active and has a longer half-life than CNP-22. Endothelial CNP plays a key role in vascular homeostasis [8]. Within the cardiac tissue, it has antihypertrophic effects on cardiac myocytes and antifibrotic effects on fibroblasts [9].

B. Natriuretic Peptide Receptors

The NP receptors NPR-A and NPR-B catalyze the synthesis of a classic intracellular second messenger, cyclic guanosine monophosphate or cGMP [2]. cGMP binds to proteins like cGMP-dependent protein kinases, cGMP-binding phosphodiesterases, and cyclic nucleotide-gated ion channels [10]. NPR-C controls the concentrations of NPs through receptor-mediated internalization and degradation [10], and NPR-A to NPR-C ratio plays a role in regulating the biological activity of NPs [11]. In addition to its clearance activity, NPR-C also possesses intrinsic activity regulating endothelial function [12], with the CNP/NPR-C signaling pathway playing a fundamental role in regulating vascular tone [8]. The binding of CNP to NPR-C has also been shown to exert a negative inotropic effect on cardiac myocytes via its inhibitory action on adenylyl cyclase activity, which inhibits L-type calcium channels through decreased cytosolic cyclic adenosine monophosphate concentrations and protein kinase A activity [9]. Animal models have demonstrated vascular relaxation and drop in blood pressures associated with administration of NPR-C agonists [7].

The other major process of degradation of NPs is mediated by the enzyme neutral endopeptidase 24.11 (neprilysin) [10, 13] (Fig. 1).

Figure 1.

Action of natriuretic peptides and receptors in target cells to maintain cardiovascular homeostasis. ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNG, cyclic nucleotide-gated ion channel; CNP, C-type natriuretic peptide; GTP, guanosine-5’-triphosphate; NEP, neprilysin; NPR-A, natriuretic peptide receptor-A; NPR-B, natriuretic peptide receptor-B; NPR-C, natriuretic peptide receptor-C; PDE, cGMP-binding phosphodiesterases; PKG, cGMP-dependent protein kinases.

C. Natriuretic Peptides and Cardiovascular Homeostasis

ANP and BNP are thought to function as defense mechanisms against ventricular stress and the deleterious effects of volume and pressure overload. They are stored together in atrial granules and secreted into the circulation in response to myocardial stretch [3]. They protect the heart from high preload and afterload by promoting diuresis and natriuresis, as well as inducing vasodilation [2]. ANP and BNP both reduce sympathetic tone and suppress renin and aldosterone secretion. The coordinated endocrine action of the NP/guanylyl cyclase system not only regulates systemic blood pressure and intravascular volume, but also plays a role in the modulation of pulmonary artery pressure and exerts local cardiac effects that counteract cardiac hypertrophy and fibrosis [3].

CNP elicits a negative inotropic response in the cardiac myocardium via the NPR-C pathway–mediated inhibition of adenylyl cyclase activity. In addition, it has been shown to exert a positive lusitropic effect via the NPR-B/cGMP pathway by amplifying the signaling of the beta-1 adrenergic receptor in chronic heart failure [9]. Endothelial CNP regulates reactivity of circulating leukocytes and platelets, systemic blood pressure, as well as distal arteriolar and capillary blood flow by exerting cGMP-mediated vasodilatory effects [14, 15]. Endothelium-derived CNP has also been shown to play a role in angiogenesis and vascular remodeling after ischemia through its NPR-C–mediated actions, suggesting a therapeutic potential in peripheral arterial disease and other ischemic cardiovascular disorders [15, 16]. Lastly, CNP also plays a role in regulation of heart rate and electrical conduction in the heart through its action on the L-type calcium channels in the sinoatrial node [16].

2. Natriuretic Peptides and Heart Failure

It is well established that patients with heart failure have elevated levels of ANP and BNP that correlate with disease severity. To explain the increased levels of these cardioprotective peptides in diseased states, several mechanisms have been described. Heart failure is associated with upregulation of proANP and proBNP with relative corin deficiency, an enzyme that is crucial for appropriate processing of NPs, thus leading to high circulating levels of unprocessed and poorly active NPs [17, 18]. Secondly, there is increased enzymatic degradation of NPs through enhanced activity of neprilysin, the peptidase that inactivates NPs. This is supported by recent clinical observations that neprilysin inhibition leads to reduced risk of hospitalization and death in heart failure patients [19]. Other mechanisms that have been postulated include increased NP cellular internalization by NPR-C, desensitization of the GC-A receptor, alteration of intracellular GC-A signaling pathways, and enhanced intracellular degradation of cGMP by phosphodiesterases 5 and 9 [3]. Target organ responsiveness to NPs is also diminished because of desensitization of NP receptors as well as reduced expression of receptors in cardiomyocytes, intramyocardial vessels, and peripheral vascular beds. In addition, overactivation of the renin-angiotensin-aldosterone system, sympathetic nervous system, and endothelin-1, all of which are antagonistic to the NP system, is seen in chronic heart failure [20]. Paulus and Tschöpe suggested a novel paradigm in the development of heart failure with preserved ejection fraction (HFpEF)—suggesting a systemic inflammatory state induced by obesity or DM, for example, causing oxidative stress, which leads to decreased myocardial nitric oxide bioavailability. This, in turn, leads to reduced protein kinase G activity, which is involved in the NP intracellular signaling pathway. This results in stiff and hypertrophied ventricles [21]. Myocardial BNP expression is also lower in HFpEF than HFrEF [22], suggesting that drugs which increase BNP levels could be a potential therapeutic strategy for HFpEF.

A. Diagnostic and Prognostic Significance of Natriuretic Peptides

The role of NT-proBNP as a predictive biomarker of all-cause and cardiovascular mortality, independent of confounders, has been well established, with a predictive value comparable to that of microalbuminuria [23]. Even small increases in baseline BNP levels were strong predictors both of left ventricular (LV) hypertrophy and diastolic dysfunction [24].

Studies have shown heart failure to be associated with increased levels of proBNP-108 in addition to BNP-32 and NT-proBNP-76 [25]. ProBNP-108 does not induce cGMP production as effectively as BNP-32. The ratio of proBNP-108 to BNP-32 is also markedly increased in patients with decompensated heart failure. The increase in proBNP-108 in heart failure, which is considered hormonally less active, results in a relative deficiency in NP, despite the total increase in the measured assay [5]. Most commercial assays cross-react with inactive or poorly active BNP-related peptides like proBNP, BNP 3-32, and junk-BNP. Patients with heart failure have an increased proportion of inactive proBNP, which contributes to reduced effectiveness of circulating BNP, impairing the compensatory actions and causing progression of heart failure [26]. Abnormalities in NP processing have also been demonstrated in prior studies—with an increase in the level of O-glycosylated proBNP but not proBNP seen in proportion to severity of heart failure [27, 28]. Increases in the levels of such hormonally less active peptides leads to an attenuation in the increase of cGMP, seen in patients with severe heart failure [4].

Despite these limitations, NPs play an important clinical role in management of heart failure. The GUIDE-IT [29] trial randomly assigned patients with heart failure with reduced ejection fraction (HFrEF) (< 40%), elevated NP levels, and a history of prior heart failure event to either an NT-proBNP–guided strategy (medical therapy titrated with the goal of achieving NT-proBNP < 1000 pg/mL) vs usual care. The study found no difference between the 2 arms. Of note, the achieved decreases in NT-proBNP levels were not significantly different between the 2 groups. On the other hand, another recent trial demonstrated that biomarker-guided intensified treatment was associated with a 65% reduction in risk of hospitalization or cardiac death in patients with DM, NT-proBNP greater than 125 pg/mL, and no known cardiac disease [30]. Thus, the present data are conflicting and call for more clinical trials with improved generalizability.

B. Natriuretic Peptides as Therapeutic Agents

In recent years, the angiotensin receptor-neprilysin inhibitor (sacubitril-valsartan) has been shown to be clinically beneficial in patients with HFrEF [31]. The benefits conferred by this drug in heart failure may be, in part, secondary to potentiating of the NPs. However, the exact mechanism remains unresolved. Synthetic ANP (also known as anaritide or carperitide) and human recombinant BNP (nesiritide) have been studied for their therapeutic role in hypertension and heart failure. Nesiritide has a significantly longer half-life than anaritide and is thought to be the better of the 2 drugs [10]. Carperitide infusions resulted in elevated sodium and water excretion along with decreased blood pressure in patients with hypertension [32] and chronic heart failure [33]. Nesiritide infusions have been associated with vasorelaxation, natriuresis, diuresis, and decreased plasma aldosterone and endothelin levels [34, 35]. Chronic subcutaneous BNP administration has been shown to improve LV remodeling, decrease LV-filling pressures, and suppress renin angiotensin while preserving glomerular filtration rate [36]. Wan et al also showed that in patients with preclinical diastolic dysfunction, chronic BNP administration led to sustained improvement in diastolic dysfunction without development of tachyphylaxis to the enhanced cardiorenal response to acute volume loading [37]. In light of these promising clinical outcomes, longer half-life BNP formulations are currently under development [38]. Although the U.S. Food and Drug Administration approved the use of nesiritide for acute decompensated heart failure in 2001, there has been some concern about increased risk of renal injury [39] and mortality [40] associated with this. This was refuted by the ASCEND-HF [41] trial, which demonstrated no increase or decrease in the rate of death, rehospitalization, or worsening renal function with the use of nesiritide. It was associated with a small, nonsignificant effect on dyspnea when used in combination with other therapies and also with an increase in the rates of hypotension. The ROSE trial by Chen and colleagues also demonstrated that neither low-dose nesiritide nor low-dose dopamine enhanced decongestion or improved renal function in patients with acute heart failure and renal dysfunction when added to standard diuretic therapy [42].

CNP does not stimulate natriuresis at physiological concentrations,

and its potential therapeutic role in cardiovascular diseases is yet to be explored [10]. However, there has been recent evidence suggesting it can prevent cardiac remodeling after an acute myocardial infarction in mice [43].

3. Natriuretic Peptides in Cardiovascular and Metabolic Cross-Talk

The discovery of the potent lipolytic effects of NPs in 2000 has led to an expansion of our understanding of their role beyond blood pressure and volume control. NPs control fatty acid mobilization from adipocytes as well as mitochondrial biology and cellular energy metabolism in adipocytes and skeletal myocytes [13].

A. Role of Natriuretic Peptides in Fat Metabolism and Glucose Handling

The NPR-A–mediated rise in cGMP and activation of protein kinase G leads to phosphorylation of hormone-sensitive lipase and perilipin, which in turn activates lipases and triggers lipolysis [44]. NPR-A activation also induces transcription of genes, leading to enhanced energy expenditure and adipocyte browning [45], modulates adipokine secretion, and has a beneficial effect on adipose inflammation and insulin resistance [2]. Several pathways have been proposed—activation of the p38 mitogen-activated protein kinase-activating transcription factor-2 and PGC1α (peroxisome proliferator-activated receptor-gamma coactivator-1α) pathways seem to be involved [13] (Fig. 2). To further the hypothesis of a “gut-heart link,” the glucagon-like peptide-1 receptors in the atrial myocardium, which are activated by a nutrient-rich meal, induce ANP secretion, thus indirectly leading to metabolic and hemodynamic changes [46]. In addition, CNP also reduces food intake and body weight through activation of the hypothalamic melanocortin pathway [47].

Figure 2.

Role of natriuretic peptides in fat metabolism and glucose handling. AMPK, 5’ adenosine monophosphate-activated protein kinase; ANP, atrial natriuretic peptide; ATGL, adipose triglyceride lipase; BNP, B-type natriuretic peptide; cGMP, cyclic guanosine monophosphate; GTP; guanosine-5’-triphosphate; HSL, hormone-sensitive lipase; MAPK, mitogen-activated protein kinase; NPR-A, natriuretic peptide receptor-A; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator-1α; PKG: cGMP-dependent protein kinases.

Coué et al demonstrated that NPR-A signaling in skeletal muscles is pivotal to the maintenance of long-term insulin sensitivity by regulating lipid oxidative capacity through a PGC1α-dependent pathway [11]. This mechanism is disrupted in obesity and DM both in mice and human models. NPR-A is also negatively associated with total body fat and muscle total saturated ceramide content—both factors that negatively influence insulin sensitivity. In addition to the role of NPR-A, upregulation in NPR-C could also contribute to the NP-handicap in reduced glucose-tolerance states [11]. The Malmö diet and cancer study suggested that low midregional ANP levels predict development of future DM [48].

The lipolytic effects of NPs, particularly BNP [1-32], are also thought to contribute to the development of cardiac cachexia in advanced heart failure through excessive fatty acid mobilization [49]. This is supported by the inverse relationship noted between NT-proBNP and reduced abdominal fat mass in cachectic states [50].

B. Genetic Variants

ANP and BNP propeptides are encoded by the genes NPPA and NPPB, respectively. Common single-nucleotide polymorphisms in the chromosomal regions containing these genes have been associated with circulating levels of NPs, which contribute to variations in blood pressure in individuals. Associations of plasma ANP with rs5068 and rs632793, and of plasma BNP with rs5068, rs198358, and rs632793 have been identified [51]. Rs5068 and rs198358 belong to the NPPA gene and rs632793 belongs to the NPPB gene. Rs5068 is a single-nucleotide polymorphism that is most strongly associated with increased plasma ANP levels, with carriers having a 15% lower risk of hypertension. The mechanism of its effect on ANP involves interference with binding of a microRNA miR-425, which is a noncoding RNA that plays a role in the posttranscriptional regulation of gene expression [52]. This variant of NPPA has also been associated with a favorable cardiometabolic profile [53] with reduced systolic blood pressure, lower prevalence of myocardial infarction, lower body mass index, lower prevalence of obesity, lower waist circumference, higher high-density lipoprotein cholesterol, lower C-reactive protein, as well as a 12% reduced adjusted-risk of incident DM [54]. Another genetic variant, rs198389 within the BNP locus, has been identified to have a potential causal role in the etiology of DM, mediated by higher NT-proBNP levels [55].

C. Natriuretic Peptide–Deficient States

Several studies have recognized that obesity is associated with lower BNP concentrations [56, 57]. Multiple hypotheses have been put forward to explain this, including increased NPR-C–mediated clearance [58] as well as decreased synthesis [59]. Decreased cardiac messenger RNA expression both of ANP and BNP has been demonstrated in obese animal models. In addition, muscle NPR-A protein is dramatically downregulated in obesity and has been shown to increase in response to diet-induced weight loss [11]. The Dallas Heart Study noted that levels of BNP and NT-proBNP were inversely associated with visceral and liver fat and positively with lower glutofemoral body fat [60]. The Atherosclerosis Risk in Communities study showed that levels of NT-proBNP in the lowest quartiles were associated with a higher risk of incident DM over a 12-year follow-up. A linear trend was also noted across the other quartiles [61].

In contrast, exercise is associated with increased circulating ANP concentrations. However, the effect on BNP appears to be less pronounced [62]. Exercise with hypocaloric dieting was found to be superior to hypocaloric dieting alone for increasing plasma levels of NT-proBNP and midregional-proANP [13]. Modest weight loss was found to reduce NPR-C messenger RNA expression, which results in decreased NP clearance [63].

Besides obesity and insulin resistance, black race/ethnicity has been identified as a state of relative NP deficiency [64, 65]. This has important physiological and clinical implications because African American individuals do have a higher prevalence of hypertension, salt sensitivity, and renal dysfunction [65].

Men have also been shown to have lower levels of NT-proBNP than age-matched women, thought to be secondary to suppression of NPs by circulating androgens [66].

D. Therapeutic Implications

Several studies have looked into the direct influence of ANP and BNP both on glucose and lipid metabolism. Studies in obese and diabetic mice have demonstrated that increasing NP levels markedly improves blood glucose control and insulin sensitivity in skeletal muscles [11]. ANP infusion in human subcutaneous tissue induces lipolysis and increases local blood flow, thus enhancing lipid metabolism [67]. Heinisch et al demonstrated that intravenous administration of BNP in healthy male individuals increased the glucose initial distribution volume and lowered plasma glucose concentrations following a glucose load, but did not affect β cell function of insulin secretion or insulin sensitivity [68]. Chronic BNP infusion was associated with a greater than 20% reduction in fasting blood glucose levels and a greater than 15% decrease in hemoglobin A1c (HbA1c) in mouse models with obesity-induced impaired glucose intolerance and type 2 DM [11]. Other studies have shown BNP infusion to decrease hunger and increase satiety, thus regulating food intake control [69]. Post hoc analysis of the PARADIGM-HF trial that established the role of sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, in patients with HFrEF noted that patients with DM and HFrEF who received sacubitril/valsartan had greater long-term reduction in HbA1c when compared to those receiving enalapril, further suggesting that modulating the NP system could enhance glycemic control [70].

4. Future Directions/Clinical Implications

There is a growing body of evidence that suggests that in addition to their role in cardiovascular homeostasis, NPs have favorable effects on fat metabolism and glucose handling. NP deficiency has been associated with an increased risk of DM. Genetic variants that cause a mild elevation of NP levels translate into a lower risk of DM and metabolic syndrome. Increased NP signaling has been associated with lower blood pressure, improved oxidative metabolism and insulin sensitivity. This raises the possibility that therapeutic strategies that enhance the production/bioavailability/activity of NPs could improve the cardiovascular and metabolic milieu in individuals. For example, sacubitril/valsartan was shown to have a greater long-term reduction in HbA1c when compared to enalapril in a post hoc analysis of the PARADIGM-HF trial [70]. Studies are under way for engineering of designer NPs [71] that could have improved receptor activation, resistance to enzymatic degradation, properties unique to a specific syndrome (eg, augmenting adipocyte activation in obesity), and even transcend the functional properties of endogenous NPs. Some such peptides currently in human trials include mutant atrial natriuretic peptide (MANP) (an ANP-like peptide with pGC-A–activating properties) as therapy for resistant hypertension, ANX-042 (an alternatively spliced BNP likely associated with pGC-B activation) as a potential nonhypotensive, renal enhancing treatment for heart failure, and cenderitide or CD-NP (targeting both pGC-A and pGC-B receptors) as therapy for postacute heart failure.

5. Conclusions

NPs play an important role in maintaining cardiovascular homeostasis and have a favorable effect on fat metabolism and glucose handling. Preliminary studies have proposed a causal association between an NP-deficient state and development of DM. This calls for research into potential therapeutic strategies to enhance NP production and/or activity that could potentially prevent or treat DM and obesity.