Heart disease is frequently perceived as a disease which mainly impacts men; however a review of epidemiological studies does not support
such a perception. Sexually divergent manifestation of heart failure has been observed in response to specific etiological factors. Heart failure
subsequent to myocardial infarction (MI) and hypertension have proven to be particularly deadly for women. Similarly, diabetes has been reported
to be a stronger risk factor for heart failure in women than in men with large population studies identifying an 8-fold increase incidence of heart
failure in women with diabetes versus a 4-fold increase in men with diabetes. Morbidity and mortality from heart failure also demonstrate significant
sexual dimorphism. Women who develop heart failure are more likely to remain symptomatic and to be more functionally limited, experience less 1 year
improvement in symptoms, and a greater rate of mortality with 62.4 percent of heart failure deaths since the year 2000 occurring in women.
Thus, while women appear to have a resilient coronary vascular phenotype, they also appear to have a “susceptible” cardiac phenotype which
is revealed subsequent to diabetes, hypertension, or MI.
Work in our laboratory has focused on two regulatory molecules expressed by cardiac cells which appear to influence sex-specific differences in the
phenotype of the remodeling heart.
For several years, we have studied the impact of the loss of signaling to the transcription factor CREB, which occurs early in the etiology of heart
failure in a plethora of rodent models. Our recent studies, utilizing on a transgenic mouse model expressing a phosphorylation-deficient CREB mutant
in a heart-specific manner, suggest that CREB dysfunction in the heart exposes mitochondrial and contractile cardiac susceptibilities in the female
sex, manifesting prior to puberty. In other words, CREB dysfunction in the context of cardiac remodeling reveals sexually-dimorphic cardiac phenotypes.
The focus of the work in my laboratory is to utilize these sex-related mitochondrial and contractile phenotypes
to access the molecular underpinnings contributing to the sexually-divergent manifestations of heart failure, and subsequent morbidity and mortality from pathological
cardiac remodeling by the sexes.
Recently, studies have been initiated in the laboratory on a newly described anti-inflammatory cytokine IL-19. Originally thought to be limited in expression to immune cells, recent work in our laboratory has demonstrated that this cytokine (1) is expressed in the heart, (2) is expressed in both cardiac myocytes and fibroblasts, (3) is differentially expressed in the heart by sex, with female hearts showing more robust expression, and (4) is modulated in its content in response to stimuli which lead to remodeling of the heart. Both isoforms of IL-19 receptors are expressed in the heart, and their relative abundance differs by sex as well. Preliminary studies indicate that IL-19 stimulation of cultured cardiac fibroblasts alters the expression of proteins essential for remodeling the extracellular matrix in the heart. This leads to speculation that IL-19 may be essential for cardiac repair in response to injuyry.
- Cardiac Failure
- Mitochondrial function
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- CREB downregulation in vascular disease: a common response to cardiovascular risk.
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- Restoration of CREB function is linked to completion and stabilization of adaptive cardiac hypertrophy in response to exercise.
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