Abstract Body: Introduction: Atrial and brain natriuretic peptides (ANP and BNP) are the cardiac peptide hormones responsible for fluid and electrolytes homeostasis, vasorelaxant, antimitogenic, and antihypertrophic responses, which lead to a reduction in blood pressure (BP), blood volume, and cardiac dysfunction. 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.

Methods: For the generation of cardiomyocyte (CM)-specific Npr1 deleted mice, a floxed Npr1 mouse line was produced with genotype of confirmed Npr1Flox/Flox (f/f) alleles. The CM-specific Cre mice having αMHC/Mer-Cre trans allele (Tamoxifen-inducible) were mated with littermate wild-type (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 WT f/f mice to generate conditional homozygous null CM-Cre;Npr1f/- (CM-KO) mice. Consecutive administration of tamoxifen (0.1 mg/g/day) for 5 days to adult (8-10 wks) male and female CM-Cre; Npr1f/- mice achieved inducible CM-specific inactivation of Npr1 in heart. The structure and function of heart were determined by ultrasound M-mode echocardiography.

Results: Our results indicated that cardiac left ventricular end-systolic and diastolic dimension (LVED-s and LVED-d), posterior wall thickness (PWT), and cardiac left ventricular hypertrophy were greatly increased in male KO mice (4.4+0.1, 3.2+0.1; p<0.05) and female KO mice (4.1+0.1, 3.2+0.2; p<0.05) compared with WT male mice (3.7+0.1, 2.3+0.1; p<0.05) and female mice (4.2+0.1, 3.1+0.1; p<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<0.005) increased in male KO mice than female KO mice compared with WT mice. The fractional shortening was significantly (p<0.05) compromised with greater magnitude in male KO mice than female KO mice in a sex-dependent manner. We found that CM-KO mice showed a decrease 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 provoked cardiac hypertrophy and dysfunction with remodeling in both sexes with higher magnitudes in males than females in a sex-specific manner. NIH grant (DK133833).