Abstract 4363352: Deletion of <i>Npr1</i> in Cardiomyocyte Provokes Cardiac Hypertrophy and Dysfunction in Mutant Mice

Abstract

Introduction: Guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) is a major biologically active natriuretic peptide (NP) receptor that synthesizes intracellular second-messenger cGMP in response to hormone binding. Atrial and brain natriuretic peptides (ANP and BNP) are the major cardiac peptide hormones responsible for fluid and electrolytes homeostasis, vasorelaxant, antiproliferative, and antihypertrophic responses, which lead to a reduction in blood pressure (BP) and cardiac dysfunction. Methods: Generation of CM-specific Npr1 deleted mice, a floxed Npr1 mouse line was generated with genotype of confirmed Npr1Flox/Flox ( f/f ) alleles. The CM-specific Cre mice having αMHC/Mer- Cre trans allele (Tamoxifen-inducible; Jackson Laboratory) were mated with WT f/f mice to generate F1 heterozygous CM- Cre;Npr1f/+ mice. The F1 hybrids having both Cre and Flox alleles were mated with original wild-type (WT) f/f mice to produce conditional homozygous null CM- Cre;Npr1f/- (CM-KO) mice. Consecutive administration of Tamoxifen (0.1 mg/g/day) for 5 days to adult (6-8 wks) male and female CM- Cre; Npr1f/- mice achieved inducible CM-specific inactivation of Npr1 in cardiomyocytes. The heart structure and function were determined by echocardiography. Results: The results showed that cardiac hypertrophy, left ventricular end-systolic and diastolic dimension (LVED-s and LVED-d), and posterior wall thickness (PWT) were significantly increased in male KO mice (4.4 + 0.1, 3.2 + 0.1; p&lt;0.05) than female KO mice (4.1 + 0.1, 3.2 + 0.2; p&lt;0.05) compared with WT male mice (3.7 + 0.1, 2.3 + 0.1; p&lt;0.05) and female mice (4.2 + 0.1, 3.1 + 0.1; p&lt;0.05). PWT was also significantly increased in both male and female KO mice compared with WT mice. Heart wight/body weight (HW/BW) ratio was significantly (p&lt;0.005) increased in male KO mice than female KO mice compared with WT mice. The fractional shortening was significantly (p&lt;0.05) compromised with greater magnitude in male KO mice than female KO mice. The f/f mice presented a more preserved contractility in the LV wall, we found that CM-KO mice showed a decreased in contractility in both sexes and this decrease was found in all parts of the LV, suggesting a weakness in the cardiomyocytes of CM-KO mice. Conclusion: The results suggest that deletion of Npr1 in cardiomyocytes provokes cardiac hypertrophy and dysfunction with remodeling in both sexes with higher magnitudes in males than females. Supported by NIH/NIDDK grant (DK133833).