Congenital heart disease (CHD) is the most common congenital abnormality and one of the leading causes of newborn death throughout the world. Despite much emerging scientific information, the precise etiology of this disease remains elusive. Here, we show that the aryl hydrocarbon receptor (AHR) regulates the expression of crucial cardiogenesis genes and that interference with endogenous AHR functions, either by gene ablation or by agonist exposure during early development, causes overlapping structural and functional cardiac abnormalities that lead to altered fetal heart physiology, including higher heart rates, right and left ventricle dilation, higher stroke volume, and reduced ejection fraction. With striking similarity between AHR knockout (Ahr(-/-)) and agonist-exposed wild type (Ahr(+/+)) embryos, in utero disruption of endogenous AHR functions converge into dysregulation of molecular mechanisms needed for attainment and maintenance of cardiac differentiation, including the pivotal signals regulated by the cardiogenic transcription factor NKH2.5, energy balance via oxidative phosphorylation and TCA cycle and global mitochondrial function and homeostasis. Our findings suggest that AHR signaling in the developing mammalian heart is central to the regulation of pathways crucial for cellular metabolism, cardiogenesis, and cardiac function, which are potential targets of environmental factors associated with CHD.
The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr -/- and in utero TCDD-exposed Ahr +/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr -/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.
The myocardial response to exercise is an adaptive mechanism that permits the heart to maintain cardiac output via improved cardiac function and development of hypertrophy. There are many overlapping mechanisms via which this occurs with calcium handling being a crucial component of this process. Our laboratory has previously found that the stretch sensitive TRPV2 channels are active regulators of calcium handling and cardiac function under baseline conditions based on our observations that TRPV2-KO mice have impaired cardiac function at baseline. The focus of this study was to determine the cardiac function of TRPV2-KO mice under exercise conditions. We measured skeletal muscle at baseline in WT and TRPV2-KO mice and subjected them to various exercise protocols and measured the cardiac response using echocardiography and molecular markers. Our results demonstrate that the TRPV2-KO mouse did not tolerate forced exercise although they became increasingly exercise tolerant with voluntary exercise. This occurs as the cardiac function deteriorates further with exercise. Thus, our conclusion is that TRPV2-KO mice have impaired cardiac functional response to exercise.
Background: Impaired calcium handling has been implicated in the development of left ventricular hypertrophy (LVH) and subsequent development of heart failure (HF). We have recently shown that the calcium channel Transient Receptor Potential Vanilloid 2 (TRPV2) is present in cardiomyocytes and regulates contractility on a beat to beat basis. This study was performed to elucidate if TRPV2 also modulates the development of LVH in a pressure overload mouse model via transverse aortic constriction (TAC). Methods: WT and TRPV2‐/‐ mice were subjected to pressure overload via TAC and followed echocardiographically for 8 weeks. A subgroup of WT mice were treated with a nonspecific TRPV2 antagonist (tranilast) for the same amount of time. At the conclusion, the hearts were collected for molecular and histological analysis of hypertrophy. Results: There was significantly less hypertrophy in TRPV2‐/‐ and in the WT mice treated with tranilast (n=5 and 2) in comparison to untreated WT mice (n=7) as noted via heart weight: body weight ratio and LV mass via echocardiography (P<0.05; TRPV2 vs. untreated WT). Furthermore, there was a trend towards improved contractility and less LV cavity dilation in the TRPV2‐/‐ and the WT treated mice in comparison to untreated mice. Conclusions: We have shown that TRPV2 modulates the development of LVH and is a potential target for the prevention and treatment of LVH and development of HF.
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