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Echocardiographic and Histological Examination of Cardiac Morphology in the Mouse
Published on: October 26, 2017
Diastolic Dysfunction with Normal Ejection Fraction and Reduced Heart Rate in Mice Expressing Human Growth Hormone
Yan Jin1, Bo Xiang2, Vernon W Dolinsky2
1Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
Insights
Human growth hormone (hGH) in mice led to reduced heart size and function, similar to growth hormone (GH) deficiency. These cardiac changes occurred despite normal growth rates and were not worsened by a high-fat diet.
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Transgenic Animal Models
Background:
- Growth hormone (GH) signaling is critical for cardiac development and function.
- Aberrant GH levels (deficiency or excess) are linked to increased cardiovascular risk.
- Human GH (hGH) and mouse GH (mGH) exhibit distinct receptor binding profiles, potentially leading to differential physiological effects.
Purpose of the Study:
- To investigate the cardiac effects of human growth hormone (hGH) expression in transgenic mice (hGH-TG) compared to wild-type (mGH-WT) mice.
- To assess cardiac structure and function using echocardiography in hGH-TG mice.
- To evaluate the impact of a high-fat diet (HFD) on cardiac parameters in hGH-TG mice.
Main Methods:
- Generation of transgenic mice expressing pituitary hGH under hypothalamic control.
- Echocardiographic analysis of cardiac structure (left ventricular mass) and function (stroke volume, cardiac output, ejection fraction, fractional shortening) in male hGH-TG and mGH-WT mice.
- Assessment of cardiac RNA markers and heart rate, including under high-fat diet conditions.
Main Results:
- Male hGH-TG mice exhibited significantly reduced left ventricular mass (48%), stroke volume (36%), and cardiac output (48%) compared to mGH-WT mice.
- hGH-TG mice showed signs of diastolic dysfunction and restrictive ventricular filling, with a lower heart rate.
- No significant differences in ejection fraction or fractional shortening were observed between groups, even after HFD; HFD did not alter cardiac damage RNA markers.
Conclusions:
- Pituitary expression of hGH in mice results in cardiac structural and functional deficits resembling GH deficiency.
- Diastolic dysfunction in hGH-TG mice may be compensated by a reduced heart rate.
- Structural cardiac alterations appear to precede functional impairments, and HFD does not exacerbate these effects in this model.
Abstract:
Growth hormone (GH) signaling is essential for heart development. Both GH deficiency and excess raise cardiovascular risk. Human (h) and mouse (m) GH differ structurally and functionally: hGH binds both the GH receptor (GHR) and prolactin receptor (PRLR), whereas mGH binds only GHR; thus, there is the potential for differential effects. We generated transgenic (hGH-TG) mice that produce pituitary hGH in response to hypothalamic signaling. These mice grow at the same rate as mGH-expressing wild-type (mGH-WT) mice but are smaller and have higher body fat. Echocardiography was used here to compare hGH-TG and mGH-WT mouse hearts. Male hGH-TG mice show a 48% lower left ventricular mass, 36% lower stroke volume, and 48% reduced cardiac output, resembling GH deficiency. Diastolic dysfunction, restrictive ventricular filling, and lower heart rate are suggested in hGH-TG mice. No significant differences in ejection fraction or fractional shortening were observed, even after high-fat diet (HFD) stress. HFD did not affect RNA markers of cardiac damage, although a possible association between B-type natriuretic peptide RNA levels and heart rate was detected. These observations suggest that diastolic dysfunction related to hGH and/or low GH might be offset by a lower heart rate, while structural changes precede functional effects.
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