It is B-type natriuretic peptide (BNP) that is the biochemical marker for heart failure that is currently clinically applicable, because heart failure so aptly describes it. NT-proBNP has no better utility than BNP in the diagnosis of heart failure. But since BNP does not metabolise like NT-proBNP in plasma and BNP is not the same substance, so BNP is not processed the same way, age does not favor NT-proBNP. In the PARADIGM-HF trial, the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril-valsartan dramatically reduced cardiovascular mortality and heart failure hospitalisation within 1 week and total mortality in patients with chronic heart failure with impaired systolic function. These results line up with recent ESC and ACC/AHA guidelines for ARNI as first-line treatment for chronic heart failure. Because BNP is also one of the activities of neprilysin, it has been demonstrated that ARNI increases plasma BNP, so that BNP does not even represent heart failure anymore.
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Structure and Amino Acid Sequence of B-type Natriuretic Peptide
B-type natriuretic peptide (BNP) stand for B-type natriuretic peptide, which the heart releases to regulate fluids and blood pressure. This BNP gene has some exons and introns where the exons are the amino acid code of protein. The adult active molecular species of human BNP is called BNP-32. BNP is a gene that's on human chromosome 1 with 3 exons and 2 introns. The 26 amino acid signal peptide and the first 15 amino acids of proBNP form exon 1. Most of the proBNP sequence is in exon 2; the terminal tyrosine and 3′-untranslated section are in exon 3. BNP mRNA splicing makes adult BNP mRNA that travels through the nuclear membrane to become 134 amino acids of preproBNP in the endoplasmic reticulum.
Fig. 1 The structure of B-type natriuretic peptide (BNP) (Nishikimi, T., et al. 2022).
Physiological Activity of B-type Natriuretic Peptide
It also churns out a hormone called B-type natriuretic peptide (BNP) that regulates fluid and blood pressure. This is most of the physiology of BNP:
Vasodilator Effect
BNP broadens blood vessels, loosens vascular smooth muscle, and decreases the resistance of the arteries which in turn lowers blood pressure. It's a phenomenon that cuts down the heartwork by putting more work on the heart.
Stimulation Renin-angiotensin-aldosterone system (RAAS)
BNP blocks the secretion of renin and hence angiotensin II and aldosterone that regulates blood pressure and salt levels.
Protection of Myocardium
BNP is an anti-inflammatory for the myocardium, it keeps the myocardial cells from growing and fibrosing, it suppresses myocardial cell death, and maintains the shape and function of the heart.
Localization and mRNA expression of B-type Natriuretic Peptide
Plasma B-type natriuretic peptide (BNP) levels in the anterior interventricular vein and coronary sinus were higher than in the aortic root suggesting that BNP is a cardiac hormone produced and released most extensively in the ventricles. proBNP is not fully degraded to BNP and NT-proBNP, but an amount of proBNP escapes into the blood unchanged. BNP mRNA is conserved with repeating AUUUA units in the 3′ untranslated area, unlike ANP mRNA. This sequence helps BNP mRNA to be degraded in the same way as the lymphokine genes and oncogenes. BNP gene expression is therefore controlled differently from ANP gene expression and is thought to be subject to dynamic changes in physiology and pathology.
B-type Natriuretic Peptide production, digestion, release, and metabolization
The transcription factor BNP is activated via the transcription factors listed above to upregulate B-type natriuretic peptide (BNP) gene expression and its transcript is translated into preproBNP in the endoplasmic reticulum. The physical stress, the ischemia, the hormones, the cytokines, etc. signaling/transcription factors activate receptors and adduce BNP gene expression. The signal peptide is taken from preproBNP by signal peptidase to create proBNP. proBNP is transferred to the Golgi machinery and phosphorylated in various levels at 7 N-terminal sites, THREONINE (Thr)36, SERINES (Ser)37, Ser44, THRONES 48, Ser53, THRONES 58 and THRONES 71.
Glycosylated proBNP then heads to the trans-Golgi network. O-linked glycosylation of proBNP at the N-terminal Thr48 and Thr71 sites is caused, at least in part, by polypeptide N-acetylgalactosamine transferase 2, and thus inducing inability to be processed by furin convertase. BNP, NT-proBNP, and proBNP therefore all get released into the blood and undergo different metabolic processes. Because circulating NT-proBNP does not adhere to BNP receptors or is degraded by enzymes like neprilysin, clearance is almost entirely up to the kidneys. Hence, NT-proBNP levels go sky high even in mild renal dysfunction and sky high in renal failure.
Conclusion
Among the natriuretic peptide family, enkephalins are very substrate-specific to ANP and CNP, and very weak to B-type natriuretic peptide (BNP). That is, enkephalins do less metabolic work to break down BNP than they do ANP. This means that activation of the natriuretic peptide/cGMP pathway is among the possible explanations for the beneficial effects of ARNI that could be due in large part to ANP rise. Immunoreactive BNP (total BNP) that increases with ARNI therapy is derived from the mature BNP that increases.
Plasma ANP went up dramatically in the early stages of ARNI treatment, and immunoreactive BNP went up modestly because mature BNP rose because enkephalin degradation declined. From there, myocardial wall stress slowly decreased, BNP gene expression declined, BNP production dropped, and finally, BNP levels in plasma declined. Proper interpretation of plasma BNP after ARNI treatment depends on understanding all the regulatory factors that influence BNP gene expression; protein manufacture, release, and metabolism; molecular receptors of BNP; BNP immunoassays; and BNP substrate specificity of neprilysin.
References
- Nishikimi, T., et al. B-Type Natriuretic Peptide (BNP) Revisited—Is BNP Still a Biomarker for Heart Failure in the Angiotensin Receptor/Neprilysin Inhibitor Era?. Biology. 2022, 11(7): 1034.
- Gachpazan, M., et al. A review of biosensors for the detection of B-type natriuretic peptide as an important cardiovascular biomarker. Analytical and Bioanalytical Chemistry. 2021, 413: 5949-5967.
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