Abstract
Cardiac hypertrophy is recognized as an independent risk factor for cardiac failure. Efficient management of hypertensive heart disease requires identification of factors that can possibly mediate the transition from hypertrophy to failure. Resident cardiac stem cells have a prominent role in the maintenance of cardiac tissue homeostasis. Decline in the proportion of healthy cardiac stem cells (CSCs) can affect tissue regeneration. In pathological conditions, apart from natural aging, an adverse microenvironment can lead to decrease in efficiency of CSCs. A systematic analysis of cardiac stem cell characteristics in pathological conditions has not been reported so far. Therefore, this study was designed with the objective of examining the age associated variation in stem cell attributes of Spontaneously hypertensive rat (SHR) in comparison with normotensive Wistar rat. Spontaneously hypertensive rat was used as the experimental model since the cardiac remodeling resembles the clinical course of hypertensive heart disease. CSCs were isolated from atrial explants. Stem cell attributes were assessed in 1-week, 6, 12 and 18-month-old male SHR, in comparison with age matched Wistar rats. In 1-week-old pups, stem cell attributes of SHR and Wistar were comparable. Migration potential, proliferative capacity, TERT expression, telomerase activity and the proportion of c-kit+ cells decreased with age, both in SHR and Wistar. DNA damage and the proportion of senescent CSCs increased with age both in SHR and Wistar rats. Age associated increase was observed in the oxidative stress of stem cells, possibly mediated by the enhanced oxidative stress in the microenvironment. The changes were more pronounced in SHR, and as early as six months of age, there was significant decrease in efficiency of CSCs of SHR compared to Wistar. The density of healthy CSCs determined as a fraction of the differentiated cells was remarkably low in 18-month-old SHR. Age associated decrease in functionally efficient CSCs was therefore accelerated in SHR. Considering the vital role of CSCs in the maintenance of a healthy myocardium, decrease in functionally efficient CSCs can be a precipitating factor in pathological cardiac remodeling. Elevated ROS levels in CSCs of SHR lends scope for speculation that decrease in efficiency of CSCs is mediated by oxidative stress; and that modulation of the microenvironment by therapeutic interventions can restore a healthy stem cell population and facilitate maintenance of cardiac homeostasis and prevent cardiac decompensation.
Highlights
Left ventricular hypertrophy (LVH) remains a powerful indicator of impending cardiac failure.[1] The cause for the progression from compensatory phase of left ventricular hypertrophy to decompensatory phase remains enigmatic
Nakamura et al observed a good correlation with age in the expression of senescence markers in cardiosphere derived cells from aged hearts; but, no correlation was observed between age and growth rate, angiogenic ability and growth factor production.[8]
Chronological age is a major determinant of the loss in growth reserve of the adult heart, dictated by progressive decline in the density and efficiency of cardiac stem cells (CSCs)
Summary
Left ventricular hypertrophy (LVH) remains a powerful indicator of impending cardiac failure.[1] The cause for the progression from compensatory phase of left ventricular hypertrophy to decompensatory phase remains enigmatic. CSCs differentiate and replace the lost myocytes; and in the event of myocardial injury, stem cells contribute towards tissue repair.[3,4] The involvement of stem cells in cardiac failure associated with age and disease has been speculated.[5,6] the temporal variation in the density and efficiency of cardiac stem cells and the effect of disease on the stem cell characteristics has not been systematically analyzed. The present study was carried out based on the premise that, “The functional efficacy of resident cardiac stem cells decrease with age and at an accelerated rate in Spontaneously hypertensive rat.”. In view of the decrease in cardiac efficiency as a function of age, the temporal variation in stem cell characteristics was assessed in normotensive Wistar rat (WST) and compared with the changes in Spontaneously hypertensive rat (SHR). The density, proliferation efficiency, migration potential, senescence and DNA damage profiles as well as oxidative stress of CSCs at different stages of cardiac remodeling were assessed
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