Cellular senescence is one of the causes of aging; senescent cells accumulate in tissues, and their inflammatory and other disruptive signaling causes considerable harm. With the newfound and rapidly spreading interest in senescent cells in the research community over the past few years, a lot of efforts are now underway to better understand how cellular senescence fits into the existing knowledge of the biochemistry of age-related conditions. Since senescent cells are a cause of chronic inflammation, and since inflammation and oxidative stress go hand in hand, near any condition in which inflammation or oxidative stress feature prominently is a good candidate for reexamination.
Recently, evidence has emerged for senescent cells to be involved in the growth and weakening of heart muscle that follows the age-related increases in blood pressure known as hypertension. Hypertension occurs because stiffening of blood vessels and dysfunction in the muscle of blood vessel walls breaks the intricate feedback system that controls blood pressure. The consequences include damage to delicate tissues, such as those of the brain and kidney, as small vessel rupture at an accelerated rate, and the aforementioned restructuring of heart muscle. The heart becomes larger and weaker. But why? The paper here looks at oxidative stress and senescent cells on heart stem cells that occurs in rats engineered to develop hypertension.
In human hearts there is 0.5 to 1% of myocyte turnover annually, envisaging the role of cardiac stem cells (CSCs) in the maintenance of cardiac tissue homeostasis. CSCs differentiate and replace the lost myocytes; and in the event of myocardial injury, stem cells contribute towards tissue repair. The involvement of stem cells in cardiac failure associated with age and disease has been speculated. However, 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.
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 heart failure. 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. This study was designed with the objective of examining the age associated variation in stem cell attributes of Spontaneously hypertensive rats (SHR) in comparison with normotensive Wistar rats. Spontaneously hypertensive rat was used as the experimental model since the cardiac remodeling resembles the clinical course of hypertensive heart disease.
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.
The expression of senescence-associated markers p21 and p16ink4a and the proportion of SA-β-gal positive cells increased with age. The proportion of senescent cells was significantly higher in SHR compared to age matched Wistar rat. Senescence and death of CSCs with increasing age in wild type mice has been implicated in impairment of growth and turnover of cells in the heart. Senescent stem cells affect their microenvironment by decreasing regenerative potential of the entire stem cell pool, while also affecting neighboring myocytes and vasculature. This study for the first time reports the increased expression of p16ink4a and p21 in CSCs with age and its preponderance in SHR. The difference between SHR and Wistar was apparent as early as 6 months of age, which is the compensatory phase of hypertrophy.
In conclusion, age associated decrease in efficiency of stem cells can be responsible for the degenerative cardiac changes in physiological aging. Aging of CSCs can affect migration and proliferation and promote apoptosis. Accelerated aging in stem cells isolated from hearts of SHR is possibly mediated by an adverse microenvironment. Decrease in the healthy stem cell pool can affect efficient tissue repair and precipitate the transition from compensated hypertrophy to cardiac failure. Enhanced oxidative stress in the microenvironment can be a predominant factor contributing to stem cell aging. The salient findings of accelerated decline in cardiac stem cell efficiency in SHR provide insight for further studies to examine whether reduction of cardiac oxidative stress can restore stem cell function and prevent progressive cardiac remodeling.