Insulin-like growth factor I (IGF-1) deficiency ameliorates sex difference in cardiac contractile function and intracellular Ca2+ homeostasis

Abstract

Sex difference in cardiac contractile function exists which may contribute to the different prevalence in cardiovascular diseases between genders. However, the precise mechanisms of action behind sex difference in cardiac function are still elusive. Given that sex difference exists in insulin-like growth factor I (IGF-1) cascade, this study is designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on sex difference in cardiac function. Echocardiographic, cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including ventricular geometry, fractional shortening, peak shortening, maximal velocity of shortening/relengthening (± dL/dt), time-to-peak shortening (TPS), time-to-90% relengthening (TR90), fura-fluorescence intensity (FFI) and intracellular Ca2+ clearance. Female C57 mice exhibited significantly higher plasma IGF-1 levels than their male counterpart. LID mice possessed comparably low IGF-1 levels in both sexes. Female C57 and LID mice displayed lower body, heart and liver weights compared to male counterparts. Echocardiographic analysis revealed larger LV mass in female C57 but not LID mice without sex difference in other cardiac geometric indices. Myocytes from female C57 mice exhibited reduced peak shortening, ± dL/dt, longer TPS, TR90 and intracellular Ca2+ clearance compared with males. Interestingly, this sex difference was greatly attenuated or abolished by IGF-1 deficiency. Female C57 mice displayed significantly decreased mRNA and protein levels of Na+-Ca2+ exchanger, SERCA2a and phosphorylated phospholamban as well as SERCA activity compared with male C57 mice. These sex differences in Ca2+ regulatory proteins were abolished or overtly attenuated by IGF-1 deficiency. In summary, our data suggested that IGF-1 deficiency may significantly attenuated or mitigate the sex difference in cardiomyocyte contractile function associated with intracellular Ca2+ regulation.

Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent

“…In the present study, a trend for lower extent of shortening and slower shortening kinetics was observed in young female versus male WT cardiomyocytes ( Supplementary Table S1). These data are consistent with the findings reported in the literature (Ceylan-Isik et al 2011;Howlett 2010). In contrast to Ceylan-Isik et al (but consistent with Howlett et al), we did not observe a difference in the time to peak myocyte shortening in young female and male myocytes.…”

“…Recently, sex differences in cardiomyocyte Ca 2+ handling have been reviewed in detail (Bell et al 2013;Parks and Howlett 2013). In WT mice, SERCA2 expression has been reported to be not different or lower in female hearts relative to male (Ceylan-Isik et al 2011;Parks and Howlett 2013). The effect of ovariectomy on SERCA2 expression decreases SERCA2 expression only with long-term hormone withdrawal (10-week duration (Bupha-Intr et al 2009;Bupha-Intr and Wattanapermpool 2006)).…”

Estrogen-IGF-1 interactions in neuroprotection: Ischemic stroke as a case study

“…However in a severe liver IGF-1 deficient mouse (LID), where males and females have similar levels of IGF-1, sex differences in cardiac myocytes are abolished. Sex differences in Ca++ regulatory proteins were specifically attenuated in IGF-1 deficient animals (Ceylan-Isik et al, 2011). Age-related changes in the cardiovascular system are also strongly modulated by sex differences in the IGF-1 system.…”

The Association of Sleep Insufficiency with Aging-related Atherosclerosis Markers: Cross-sectional Study

“…Furthermore, IGF-1 has been associated with osteoporosis mostly in women 15) , while association with lean body mass in men 16) . In fact, IGF-1 secretion differs by gender 17) . The reason of gender differences of our study for IGF-1 which was significant only in men could not be determined.…”