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Development of Hypertension and Cardiac Hypertrophy is associated with Endothelial Cell Dysfunction in Npr1 Gene‐disrupted Mice
Author(s) -
Das Subhankar,
Noland Whitney,
Periasamy Ramu,
Krazit Stephen T.,
Pandey Kailash N.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.07079
Subject(s) - npr1 , medicine , endocrinology , atrial natriuretic peptide , natriuretic peptide , npr2 , blood pressure , brain natriuretic peptide , biology , heart failure
Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones that elicit natriuretic, diuretic, vasorelaxant, and antiproliferative responses, all of which contribute to lowering blood pressure and blood volume. ANP and BNP bind to guanylyl cyclase ‐A/natriuretic peptide receptor ‐A (GC‐A/NPRA), which is considered to be the major natriuretic peptide receptor that synthesizes the intracellular second messenger cGMP. The objective of the present study was to examine the effect of Npr1 (coding for NPRA) gene‐disruption on the process of endothelial cell dysfunction in the development of hypertension and cardiac hypertrophy. We used six‐month old mice having different copies of Npr1 gene (0‐copy, 1‐copy, and 2‐copy). The blood pressure and echocardiographic measurements were performed in each group. Blood was collected by direct cardiac puncture and cardiac tissues were harvested and snap frozen in liquid nitrogen. The 0‐copy ( Npr1 −/− ) mice showed 35–45 mmHg higher systolic blood pressure (SBP) as compared to 2‐copy ( Npr1 +/+ ) mice. Echocardiographic measurements of Npr1 gene‐disrupted 1‐copy ( Npr1 +/− ) and 0‐copy mice showed significant increased LVEDD (27% in 0‐copy and 10% in 1‐copy mice), intraventricular septal wall thickness (IVSTDD, 30% in 0‐copy and 15% in 1‐copy mice), and reduced fractional shortening by 24% in 0‐copy and 12% in 1‐copy mice as compared with control mice. There was also a significant increase in plasma levels of plasminogen activator inhibitor‐1 (PAI‐1; 2.2‐fold), soluble intracellular adhesion molecule (sICAM; 1.8‐fold), soluble vascular cell adhesion molecule (sVCAM; 30%). In the present study, increased plasma levels of sICAM, sVCAM, and PAI‐1 suggested the involvement of endothelial cell dysfunction in producing cardiac hypertrophy in Npr1 null mutant mice. Our results implicate that ANP/NPRA signaling promotes inhibitory effect on the agents, which cause endothelial dysfunction in the heart leading to cardiac hypertrophy and cardiac remodeling. Support or Funding Information This work was supported by NIH grant (HL062147).