Introduction The prevalence of heart failure with preserved ejection fraction (HFpEF)
is continuously rising and predominantly affects older women often hypertensive and/or
obese or diabetic. Indeed, there is evidence on sex differences in the development
of HF. Hence, we studied cardiovascular performance dependent on sex and age as well
as pathomechanisms on a cellular and molecular level.Methods We studied 15-week- and
1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin
gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked
blood pressure and cardiac function via echocardiography. After sacrificing the 1-year
survivors we studied vascular smooth muscle and endothelial function. Isolated single
skinned cardiomyocytes were used to determine passive stiffness and Ca2+-dependent
force. In addition, Western blots were applied to analyse the phosphorylation status
of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII
as well as their expression. Protein kinase activity assays were used to measure activities
of CaMKII, PKG and angiotensin-converting enzyme (ACE).Results TG male rats showed
significantly higher mortality at 1 year than females or WT male rats. Left ventricular
(LV) ejection fraction was specifically reduced in male, but not in female TG rats,
while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased
LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation
were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte
function showing different response to acetylcholine and Ca2+-sensitivity of force
production, respectively cardiomyocyte functional changes were associated with altered
phosphorylation states of cardiac myosin binding protein C and cardiac troponin I
phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in
TG animals. On a molecular level titin phosphorylation pattern was altered, though
alterations were sex-specific. Thus, also the reduction of PKG expression and activity
was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored
by PKG and CaMKII treatments in both TG sexes.Conclusion Here we demonstrated divergent
sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin
system in the rat. Higher mortality of male TG rats in contrast to female TG rats
was observed as well as reduced LV systolic function, whereas females mainly developed
HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired
titin function contributes to a sex-specific molecular mechanism. The functional derangements
of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.
