Aging, MicroRNAs, and Heart Failure

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Abstract

Aging is a major risk factor for heart failure, one of the leading causes of death in Western society. The mechanisms that underlie the different forms of heart failure have been elucidated only in part and the role of noncoding RNAs is still poorly characterized. Specifically, microRNAs (miRNAs), a class of small noncoding RNAs that can modulate gene expression at the posttranscriptional level in all cells, including myocardial and vascular cells, have been shown to play a role in heart failure with reduced ejection fraction. In contrast, miRNAs role in heart failure with preserved ejection fraction, the predominant form of heart failure in the elderly, is still unknown. In this review, we will focus on age-dependent miRNAs in heart failure and on some other conditions that are prevalent in the elderly and are frequently associated with heart failure with preserved ejection fraction.

Introduction

Aging is a major risk factor for cardiovascular diseases (CVD), which represent more than 30% of all deaths worldwide. As the average human lifespan continues to increase, the prevalence of age-associated diseases including heart failure (HF), hypertension, and diabetes is assuming epidemic proportions.

Aging is characterized by the decline of the physiological functions necessary for survival and reproduction. During aging, a progressive deterioration of cellular processes occurs in all tissues and all cell functions are involved in association with distinct biologic characteristics, including genomic stability due to the accumulation of DNA damage and impairment of DNA repair1; continuous shortening of telomeres2; variations in control of gene expression, such as epigenetic and alternative splicing3, 4; cellular senescence5; dysfunctions in mitochondria metabolism6 and protein homeostasis7; and enhanced oxidative stress.8

Aging per se modifies myocardial and vascular function even in the absence of clinical disease. The aging heart exhibits progressive structural and functional changes such as left ventricular hypertrophy, which is associated with a delay in ventricular relaxation, and changes in diastolic intracellular calcium dynamics (Fig 1A). Both heart failure with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF) are very common in older persons and frequently coexist in the same patient. Specifically, HFpEF affects approximately 70% of elderly individuals with heart failure9; in fact, at the time of diagnosis, most of the patients with HFpEF are more than 60 years old10 and is more common in women than in men with a 2:1 ratio.9

It is noteworthy that the presence of diastolic dysfunction associated to a left ventricular ejection fraction >50% is not diagnostic for HFpEF and that clinical evidence of HF is also required. Mechanisms responsible for HFpEF are poorly characterized, although there is some evidence to support a role for low-grade inflammation,11 microvascular endothelial dysfunction,12, 13 cardiomyocyte hypertrophy,14 and enhanced fibrosis,15 ultimately leading to an increase in cardiac stiffness and impaired relaxation.16 Further, certain conditions, including hypertension,17 obesity,18 and diabetes mellitus,19 are frequent comorbidities associated with HFpEF. Elucidation of the mechanisms responsible for HFpEF is a major health priority, not only because of the large number of patients involved but also because therapeutic strategies are limited to diuretics and optimal fluid balance. This is in stark contrast to the large array of pharmacologic and nonpharmacologic treatment options in patients with HFrEF.

Section snippets

microRNAs’ Function and CVD

microRNAs (miRNAs) are short noncoding RNAs, approximately 22 nucleotides long, that regulate the expression of miRNA targets in a sequence specific manner, through the induction of miRNA degradation or translational repression.20 miRNAs modulate a variety of important cell functions including stem cell self-renewal, cell proliferation, apoptosis, metabolism, and oxidative stress,21 and have been recently considered relevant regulators of cellular senescence and aging.22 Numerous studies have

miRNAs in Aging and HF

In this review we will discuss miRNAs that may be involved in HF and examine separately miRNAs that exhibit an age-dependent modulation in the heart, in tissues other than the heart and miRNAs that may help differentiate HFpEF vs HFrEF.

Conclusions

Literature discussed in this review shows that some age-dependent miRNAs play a key role in HFrEF and suggest that they may be important therapeutic targets to improve heart function, either via their downmodulation or overexpression. Further, there are several reports that have examined age-modulated miRNAs in HF but have not established whether age-dependent changes in expression of these miRNAs occurred also in the heart. We summarized the effect of miRNAs modulated by aging and senescence

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    Source of funding: This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health to M.C.F., E.G.L., and M.C.C. and by the Italian Ministry of Health RF-2016-02362708 to A.M., S.B., and M.C.C.

    1

    These authors contributed equally to this work.

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