Key result
Loss of ADAM15 in male mice subjected to pressure overload exacerbated decompensated hypertrophy and dilation via calcineurin pathway activation, whereas female mice were protected.
Why the study?
The role of membrane-bound ADAM proteinases in heart disease remains underexplored, although ADAM15 is downregulated in failing human hearts.
Loss of ADAM15 exacerbates pressure overload-induced cardiomyopathy in male but not female mice, likely due to sex-dependent differences in calcineurin-mediated signaling.
Sex-specific worsening of pressure-overload cardiomyopathy in Adam15-/- male mice is hypothesis-generating; leaves open ADAM15 as a therapeutic target in human heart failure.
Cardiac dysfunction associated with cardiomyopathies is characterized by myocardial hypertrophy and dilation involving many cellular and molecular signalling events. A disintegrin and metalloproteinases (ADAMs) are membrane-bound proteinases with diverse functions, whose role in heart disease remains underexplored. ADAM15 is expressed in the heart and is downregulated in the failing human heart. In left ventricular (LV) specimens, ADAM15 levels did not change in patients with concentric hypertrophy (preserved ejection fraction) but was markedly decreased in hypertrophic and dilated failing cardiomyopathy. We investigated the role of ADAM15 in pressure overloaded cardiomyopathy in both male and female C57BL/6 mice. Loss of ADAM15 alone did not cause cardiomyopathy in both male and female mice up to 1 year of age. Male and female wildtype (WT) and ADAM15 knockout ( Adam15 -/- ) mice were subjected to cardiac pressure overload by transverse aortic constriction (TAC) at 8 weeks of age. Adam15 -/- female mice had comparable cardiac function and hypertrophy to their WT controls while, Adam15 -/- male mice exhibited worsened decompensated hypertrophy and dilation with increased activation of mitogen activated protein kinases (pJNK, pERK1/2) compared to WT. Expression of integrin-α7 (but not integrin β1) increased significantly more in male Adam15 -/- -TAC hearts, while the interaction of integrins with basement membrane (laminin) decreased consistent with increased LV dilation. Activity of calcineurin was higher in male Adam15 -/- -TAC hearts along with greater de-phosphorylation of its target transcription factor, NFAT1. Calcineurin inhibition (cyclosporin A) blocked the excess hypertrophy and dilation in male Adam15 -/- mice post-TAC. Calcineurin signalling has been shown to be inhibited by 17β-estradiol (E2), the circulating form of estrogen. Thus, the sex-dependent phenotypic differences in male and female Adam15 -/- mice following pressure overload could be attributed to the inherent increased inhibition of calcineurin-mediated signalling due to the increased expression of estrogen in female mice. Research supported by Canadian Institutes of Health Research (CIHR) grant This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Aujla et al. (2023) studied Pressure overloaded cardiomyopathy. ADAM15 knockout (Adam15 -/-) vs. Wildtype (WT) mice was evaluated on Cardiac hypertrophy and dilation. Loss of ADAM15 in male mice subjected to pressure overload exacerbated decompensated hypertrophy and dilation via calcineurin pathway activation, whereas female mice were protected.
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