Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation

Shi, Wei; Sheng, Xuanyu; Dorr, Kerry M.; Hutton, Josiah E.; Emerson, James I.; Davies, Haley A.; Andrade, Tia D.; Wasson, Lauren; Greco, Todd M.; Hashimoto, Yutaka; Federspiel, Joel D.; Robbe, Zachary L.; Chen, Xuqi; Arnold, Arthur P.; Cristea, Ileana M.; Conlon, Frank L.

doi:10.1016/j.devcel.2021.09.022

Cited by 50 publications

(48 citation statements)

References 101 publications

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“…These findings of cardiac recovery in the male but not female sFR-Refed rat indicate that during the refeeding period male heart function was able to recover from the acute effects of sFR-induced injury. One contributing factor is likely related to differences in sex chromosomes and the organizational and activational effects of sex hormones [ 21 , 22 ]. Testosterone exposure in utero , during development and after gonadal hormone maturity has profound growth promoting effects on muscle mass.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of female rats to cardiac arrhythmias following refeeding after severe food restriction

et al. 2022

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Background Many studies have shown malnutrition and inadequate caloric consumption have adverse acute effects on cardiovascular structure and function. Methods To determine the adverse long term cardiovascular effects, we studied cardiac morphology and function in female (F) and male (M) severe food restricted rats 3 months after refeeding (sFR-Refed). Results Two weeks of a normal chow diet in which calories were reduced by 60% decreased body weight (BW) by approximately 15% in both sexes. Within 2 weeks of refeeding, no differences in BW were detected between CT and sFR-Refed groups. However, male rats gained almost 3 times more BW than the females over the 3-month refeeding period. Sex differences were also observed in cardiac pathology. Hearts from F-sFR-Refed rats exhibited more atrophy and less hypertrophy, while M-sFR-Refed rats predominantly exhibited hypertrophic remodeling. While there were no differences in the frequency of ventricular arrhythmias induced by ischemia/reperfusion (I/R) in the isolated heart between M-CT and M-sFR-Refed rats, I/R induced twice as many arrhythmias in the F-sFR-Refed rats compared to F-CT. Conclusions These findings indicate the female heart is more susceptible to the long term adverse cardiovascular effects of sFR months after refeeding. Thus, this study provides a rationale for studying sex differences in cardiovascular risk in individuals who experience sFR for voluntary (e.g., very low-calorie dieting) or involuntary (e.g., poverty) reasons earlier in life.

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Section: Discussionmentioning

confidence: 99%

Susceptibility of female rats to cardiac arrhythmias following refeeding after severe food restriction

et al. 2022

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“…We recently reported significant differences in the cardiac transcriptome that are apparent before the onset of major sex hormones and sexual maturity, as well as in the hearts of reproductively incompetent aged females [ 49 ] . The cardiac proteome also appears to develop differently between males and females, independent of sex hormones [ 94 ] , given the robust differences in proteomics in mice at embryonic day E9.5, with gonadal development occurring at day Ell. When sex hormones cannot explain sex differences, either due to the persistence of sex differences post removal of gonads, it is logical to conclude that non-hormone mediated mechanisms must be contributing.…”

Section: Mechanisms Of Sex Differences In Cardiac Agingmentioning

confidence: 99%

Mechanisms and implications of sex differences in cardiac aging

Yusifov¹,

Woulfe²,

Bruns³

2022

JCA

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Aging promotes structural and functional remodeling of the heart, even in the absence of external factors. There is growing clinical and experimental evidence supporting the existence of sex-specific patterns of cardiac aging, and in some cases, these sex differences emerge early in life. Despite efforts to identify sex-specific differences in cardiac aging, understanding how these differences are established and regulated remains limited. In addition to contributing to sex differences in age-related heart disease, sex differences also appear to underlie differential responses to cardiac stress such as adrenergic activation. Identifying the underlying mechanisms of sex-specific differences may facilitate the characterization of underlying heart disease phenotypes, with the ultimate goal of utilizing sex-specific therapeutic approaches for cardiac disease. The purpose of this review is to discuss the mechanisms and implications of sex-specific cardiac aging, how these changes render the heart more susceptible to disease, and how we can target age- and sex-specific differences to advance therapies for both male and female patients.

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“…Using XO mice generated as an animal model for TS, a recent study identified X-linked cardiac proteins as being differentially regulated between XO and XX mice [ 71 ]. Although these findings are important for understanding the relationship between sex chromosome proteins and cardiovascular abnormalities, species-specific differences exist in primary and secondary sex determination, gametogenesis and reproduction.…”

Section: Cardiovascular Manifestations In Sex Chromosome Disordersmentioning

confidence: 99%

“…Furthermore, X-Y homolog genes have not contributed to the discovery of a potential genetic mechanism for cardiac defects in patients with TS. It is possible that the answers lie in genes that escape X-inactivation, in more complex post-transcriptional mechanisms such as microRNA regulation and splicing, or in epigenetic mechanisms, which are thought to contribute to sex differences in cardiac development and malformations [ 65 , 71 , 78 , 79 ]. Importantly, given the gonadal insufficiency and the resulting abnormal production of sex hormones, such as E2, in patients with TS [ 80 ], it is highly likely that at least some of the TS cardiovascular abnormalities arise in response to hormonal defects.…”

Section: Cardiovascular Manifestations In Sex Chromosome Disordersmentioning

confidence: 99%

“…In contrast, primary and secondary sex determination in humans occur during embryonic development in a Y-chromosome-dependent manner. Interestingly, a recent study suggested that cardiac differences between males and females first appear at the embryo stage, thus following a sex-chromosome-dependent mechanism [ 71 ]. This early sex determination may account for the inability of humans to generate new cardiomyocytes ( Figure 2 ).…”

Section: Cardiac Regeneration and Repair: Effects Of Biological Sexmentioning

confidence: 99%

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Sex-Related Effects on Cardiac Development and Disease

Siokatas

Papatheodorou

Daiou

et al. 2022

JCDD

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Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality. Interestingly, male and female patients with CVD exhibit distinct epidemiological and pathophysiological characteristics, implying a potentially important role for primary and secondary sex determination factors in heart development, aging, disease and therapeutic responses. Here, we provide a concise review of the field and discuss current gaps in knowledge as a step towards elucidating the “sex determination–heart axis”. We specifically focus on cardiovascular manifestations of abnormal sex determination in humans, such as in Turner and Klinefelter syndromes, as well as on the differences in cardiac regenerative potential between species with plastic and non-plastic sexual phenotypes. Sex-biased cardiac repair mechanisms are also discussed with a focus on the role of the steroid hormone 17β-estradiol. Understanding the “sex determination–heart axis” may offer new therapeutic possibilities for enhanced cardiac regeneration and/or repair post-injury.

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Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation

Cited by 50 publications

References 101 publications

Susceptibility of female rats to cardiac arrhythmias following refeeding after severe food restriction

Susceptibility of female rats to cardiac arrhythmias following refeeding after severe food restriction

Mechanisms and implications of sex differences in cardiac aging

Sex-Related Effects on Cardiac Development and Disease

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