Increased myocardial collagen and ventricular diastolic dysfunction in relaxin deficient mice: a gender-specific phenotype

Objective: To investigate cardiac phenotypes in mice deficient in the peptide hormone relaxin by gene targeting. Methods: Echocardiography and cardiac catheterization were performed on male and female relaxin deficient (Rlx(-/-)) mice as well as heterozygous (Rlx(+/-)) and wildtype (Rlx(+/+)) littermates aged between 8 and 24 months. Collagen expression and content in the heart were analysed by real-time PCR, hydroxyproline assay and histology. Results: Heart rate, blood pressures, left ventricular (LV) dimensions, fractional shortening and maximal and minimal dP/dt did not differ significantly between the three genotypes of either gender at any age. However, 8-10-month-old Rlx(-/-) males exhibited a greater transmitral flow velocity (A-wave) at the late LV diastolic phase. Male Rlx(-/-) mice aged between 12 and 24 months had significantly higher LV end-diastolic pressures, a 30% increase in atria] weight and 10-30% increases in lung and liver weights. Male mice also showed an age-dependent increase (P<0.01) in LV collagen content that was more pronounced in Rlx(-/-) than control littermates (P<0.01). Procollagen type-1 expression was also significantly higher in the LV of Rlx(-/-) males compared with either Rlx(+/-) or Rlx(+/+) males at 6, 9 and 12 months of age. Age-matched female Rlx(-/-) mice did not display any of these cardiac phenotypes seen in Rlx(-/-) males. Conclusions: Male Rlx(-/-) mice had impeded LV diastolic filling and increased atrial weights, most likely due to an increase in ventricular collagen content and chamber stiffness. These phenotypes in the Rlx(-/-) males were not observed in Rlx(-/-) females, indicating the importance of other gender-related factors in cardiovascular function. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.