Matters of the heart: Cellular sex differences

Walker, Cierra J.; Schroeder, Megan E.; Aguado, Brian A.; Anseth, Kristi S.; Leinwand, Leslie A.

doi:10.1016/j.yjmcc.2021.04.010

Cited by 43 publications

(38 citation statements)

References 196 publications

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“…Along these lines, we observed that HDAC inhibition significantly upregulated the expression of genes whose expression was lost in the POLG mutant, reinforcing the notion of zinc dependent HDAC inhibition as a potentially beneficial therapeutic strategy. This work highlights the degree to which alternate environmental exposures can modulate the presentation of pathology arising from the same genetic mutation and observed sex differences reiterate the complexities of sex-dependent responses to metabolic insult (30)(31)(32)(33). Importantly, we provide a unique dataset to the field, which will allow hypothesis generation for investigation of cardiac RV physiology and function.…”

Section: Discussionmentioning

confidence: 77%

“…This work highlights the degree to which alternate environmental exposures can modulate the presentation of pathology arising from the same genetic mutation and observed sex differences reiterate the complexities of sex-dependent responses to metabolic insult ( 30–33 ). Importantly, we provide a unique dataset to the field, which will allow hypothesis generation for investigation of cardiac RV physiology and function.…”

Section: Discussionmentioning

confidence: 80%

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Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

Gorr

Francois

Marcho

et al. 2022

Preprint

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Aging is associated with metabolic dysfunction and metabolic dysfunction accelerates the course of aging. This is well illustrated by aging-like phenotypes displayed in the Polymerase Gamma mutant mouse. Here, a key residue of the mitochondrial DNA polymerase is mutated (D257A) which hinders proof reading capacity, resulting in mitochondrial DNA mutation and instability. Given known cardiac phenotypes in the POLG mutant mouse, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies. Including both male and female animals allowed interrogation of sex-specific responses to severe metabolic dysfunction. We also conducted RNA-seq analysis on cardiac right ventricles to broadly identify mechanisms engaged by severe metabolic dysfunction that are associated with RV pathology. Several interesting sex differences were noted. Specifically, female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male POLG mutants showed LV wall thinning while female POLG mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. Finally, RNA-seq analysis of the RV tissue indicated that POLG mutation significantly impacted canonical pathways associated with inflammation, fibrosis, and heart failure. Comparison of this RNA-seq dataset with other publically available datasets highlight 1) strong conservation among downregulated genes in models of accelerated cardiac aging, 2) the potential involvement of the mitochondrial unfolded protein response in the POLG mutant, and 3) the ability of zinc dependent HDAC inhibition to rescue the expression of genes downregulated in accelerated cardiac aging.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 80%

Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

Gorr

Francois

Marcho

et al. 2022

Preprint

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“…Alternatively, it is possible that differences between the groups would manifest in later adulthood or in response to pathological cues. In addition, in our study, we used males and females which could explain the lack of differences between mouse strains since sex differences have been reported in preclinical (26) and clinical studies (27,28). A diet variation may be used to create pathological conditions; for example, mice could be put under different types of diets such as celecoxib to manipulate glucocorticoid signaling to create a more permissive environment for the appearance of cardiac diseases (29).…”

Section: Discussionmentioning

confidence: 99%

Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

Nasim

Pandey

Kanashiro‐Takeuchi

et al. 2021

Front. Cardiovasc. Med.

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The aortic valve (AoV) maintains unidirectional blood distribution from the left ventricle of the heart to the aorta for systemic circulation. The AoV leaflets rely on a precise extracellular matrix microarchitecture of collagen, elastin, and proteoglycans for appropriate biomechanical performance. We have previously demonstrated a relationship between the presence of pigment in the mouse AoV with elastic fiber patterning using multiphoton imaging. Here, we extended those findings using wholemount confocal microscopy revealing that elastic fibers were diminished in the AoV of hypopigmented mice (KitWv and albino) and were disorganized in the AoV of K5-Edn3 transgenic hyperpigmented mice when compared to wild type C57BL/6J mice. We further used atomic force microscopy to measure stiffness differences in the wholemount AoV leaflets of mice with different levels of pigmentation. We show that AoV leaflets of K5-Edn3 had overall higher stiffness (4.42 ± 0.35 kPa) when compared to those from KitWv (2.22 ± 0.21 kPa), albino (2.45 ± 0.16 kPa), and C57BL/6J (3.0 ± 0.16 kPa) mice. Despite the striking elastic fiber phenotype and noted stiffness differences, adult mutant mice were found to have no overt cardiac differences as measured by echocardiography. Our results indicate that pigmentation, but not melanocytes, is required for proper elastic fiber organization in the mouse AoV and dictates its biomechanical properties.

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“…Of note, data from knockout animal/MI studies that we address in this review originate either from animals of both sexes or the specific sex was not mentioned. Thus, we cannot comment on potential gender-specific effects of neurotrophin/TGFβ signaling in MI [95].…”

Section: A Brief Overview: Ischemic Heart Disease and Myocardial Infarction (Mi)mentioning

confidence: 96%

TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

et al. 2021

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Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.

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Matters of the heart: Cellular sex differences

Cited by 43 publications

References 196 publications

Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

Pigmentation Affects Elastic Fiber Patterning and Biomechanical Behavior of the Murine Aortic Valve

TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

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