
-   Different neurohormonal stimuli, including angiotensin II, endothelin-1, arginine vasopressin, adrenergic agonists, growth factors and cytokines (tumor necrosis factor and interleukins-1 and 6), glucocorticoids, thyroid hormones, sex steroids, and the incretin glucagon-like peptide-1 (GLP1), may promote increased secretion of NPs [PMID: 23542788, PMID: 36982204].
-   The neurohormonal stimuli regulate the expression of NPPA through the transcriptional factors RAS/c-Raf-1 and the phosphoinositide signaling pathways which stimulate the p38-mitogen-activated protein kinase (MAPK) [PMID: 23542788, PMID: 28864549].
-   The NPs binding to NPR-A and NPR-B cause the intracellular formation of cyclic guanylate monophosphate (cGMP) whose intracellular targets are cGMP-dependent protein kinases (PKGs), cGMP-gated ion channels, and cGMP-regulated cyclic nucleotide phosphodiesterases [PMID: 8914042]. And the cGMP/PKG pathway is a common mediator of cardioprotection.
-   The ablation of NPPA or NPR1 (the gene encoding NPR-A) as well as NP genetic variants leading to reduced peptide expression have been associated with cardiac hypertrophy and impaired endothelial cell viability and proliferation. The decreased viability of Npr1(-/-) embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility [PMID: 19782130].
-   GLTSCR1 deletion promoted NPPA expression by coordinating the CHD risk G allele of rs56153133 in the NPPA enhancer and releasing the transcription factor ZNF740-binding site on the NPPA promoter, which led to embryonic lethality in mice with severe congenital heart defects (CHDs) [PMID: 36745292].
-   Ras inhibits Jun-activated human atrial natriuretic peptide gene transcription in cultured ventricular myocytes [PMID: 9118490].

## Summary

The NPPA gene encodes for the atrial natriuretic peptide (ANP), which functions as a homeostatic balancer of cardiovascular and renal activities [CS: 9]. The gene is upregulated in response to increased cardiac stress or volume overload, leading to the secretion of ANP [CS: 8]. ANP counteracts these stressors by binding to natriuretic peptide receptor A (NPR-A), leading to the production of cyclic guanosine monophosphate (cGMP) [CS: 9]. cGMP then activates protein kinase G (PKG), which promotes vasodilation, reducing blood pressure, and increases natriuresis and diuresis, reducing blood volume [CS: 9]. These actions of ANP serve to alleviate the mechanical stress on the heart by lowering the workload and preventing the maladaptive hypertrophic response [CS: 8].

In heart diseases and toxic events like cardiac hypertrophy or hypertension, the persistent mechanical overload can trigger the upregulation of NPPA as the heart tries to reduce the increased blood volume and pressure through the mechanisms described above [CS: 8]. However, in the case of NPPA dysregulation, where the gene's expression is impaired or its function is altered due to mutations, this compensatory mechanism is inadequate [CS: 7]. Without the proper functioning of ANP, the heart cannot effectively reduce the mechanical strain, leading to unchecked hypertrophy and remodeling, contributing to the progression of heart disease [CS: 7].
