A Systems Biology Approach to Investigating Sex Differences in Cardiac Hypertrophy

AbstractMany pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene activity map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 20.1% of the gene activity is influenced by sex. For example, skeletal muscle was predominantly enriched with genes more active in males, whereas thyroid primarily contained genes more active in females. This was accompanied by consistent sex differences in pathway activity, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene activity over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are known druggable targets. This emphasizes sex as a biological variable and the need to incorporate sex in systems biology studies.

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A role for PPARα in sex differences in cardiac hypertrophy

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2017.07.036 ◽

2017 ◽

Vol 112 ◽

pp. 141-142

Author(s):

Natasha Fillmore ◽

Josephine Harrington ◽

Shouguo Gao ◽

Yanqin Yang ◽

Xue Zhang ◽

...

Keyword(s):

Sex Differences ◽

Cardiac Hypertrophy

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The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01283.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. H1514-H1522 ◽

Cited By ~ 23

Author(s):

James R. Bell ◽

Enzo R. Porrello ◽

Catherine E. Huggins ◽

Stephen B. Harrap ◽

Lea M. D. Delbridge

Keyword(s):

Sex Differences ◽

Cardiac Hypertrophy ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Cardiac Ischemia ◽

Normal Heart ◽

Intrinsic Resistance ◽

Ischemic Insult ◽

First Derivative ◽

Disease Outcomes

Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (I/R) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 ± 0.49 vs. 4.80 ± 0.10 mg/g; P < 0.05) and male (5.76 ± 0.22 vs. 4.62 ± 0.07 mg/g; P < 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/d tmax): NHR, 4,036 ± 171 vs. 4,258 ± 152 mmHg/s; and HHR, 3,974 ± 160 vs. 4,540 ± 259 mmHg/s; P < 0.05]. HHR hearts were more susceptible to I/R (I = 25 min, and R = 30 min) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/d tmax) post-I/R relative to male NHR (95.0 ± 12.2% vs. 60.5 ± 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 ± 5.6% vs. 25.9 ± 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to I/R insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.

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Sex Differences in Arteriovenous Fistula-induced Cardiac Hypertrophy Lead to Similar Cardioprotective Adaptation

JVS: Vascular Science ◽

10.1016/j.jvssci.2021.09.007 ◽

2021 ◽

Author(s):

Shin-Rong Lee ◽

Stephanie Thorn ◽

Nicole Guerrera ◽

Luis A. Gonzalez ◽

Ryosuke Taniguchi ◽

...

Keyword(s):

Sex Differences ◽

Cardiac Hypertrophy ◽

Arteriovenous Fistula

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Abstract 255: Sex Differences in Survival, Ventricular Remodeling, and Cardiomyocyte Contractility After Isoproterenol

Circulation Research ◽

10.1161/res.121.suppl_1.255 ◽

2017 ◽

Vol 121 (suppl_1) ◽

Author(s):

Angela K Peter ◽

Christa L Trexler ◽

Kimberly R Lugo ◽

Amy R Perry ◽

Leslie A Leinwand

Keyword(s):

Sex Differences ◽

Cardiac Hypertrophy ◽

Adrenergic Receptor ◽

Ventricular Remodeling ◽

Ventricular Myocytes ◽

Female Rats ◽

Preclinical Research ◽

Male And Female ◽

Male And Female Rats

Introduction: Significant sexual dimorphisms have been demonstrated to be important modifiers of cardiovascular disease (CVD). However, women have traditionally been omitted from clinical trials and female animals have been excluded from most preclinical research studies, ultimately leading to therapeutics that are not as effective, or with different side effects, in women relative to men. In light of the effects that sex has on CVD, the National Institutes of Health has called for the inclusion of both male and female animals in preclinical CVD research. Methods and Results: Through recent RNAseq experiments, we found both the α- and β-adrenergic receptors were significantly increased in isolated female adult rat ventricular myocytes (ARVMs) when compared to male ARVMs. In order to test whether this difference in gene expression translated to functional differences, the β-adrenergic receptor agonist, isoproterenol (ISO), was utilized to induce pathological cardiac hypertrophy in male and female rats. Survival of both sexes following a 7 day ISO treatment was significantly lower compared to vehicle. In addition, male ISO treated rats had significantly lower survival compared to female ISO treated rats (44% survival versus 77% survival, respectively). Both sexes developed significant cardiac hypertrophy compared to vehicle controls, but male ISO treated rats developed greater cardiac hypertrophy compared to ISO treated females. ARVM contractility experiments revealed no significant increases in peak shortening in response to ISO treatment in either sex. However, in both sexes, ARVMs isolated from ISO treated animals took less time to reach peak shortening and displayed increased departure velocity. Conversely, only male ISO treated ARVMs took less time to relax, exhibiting an increase in return velocity. Conclusions: Chronic in vivo β-adrenergic receptor stimulation revealed dramatic sex differences both in the intact heart and at the cellular level including increased mortality, increased cardiac hypertrophy, and altered myocyte contractility in males compared to females. These findings suggest that 7 day ISO treatment in rats may serve as a reliable, reproducible animal model for testing current and future CVD therapeutics in both sexes.

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