Myocardial aging as a T-cell–mediated phenomenon

Abstract

In recent years, the myocardium has been rediscovered under the lenses of immunology, and lymphocytes have been implicated in the pathogenesis of cardiomyopathies with different etiologies. Aging is an important risk factor for heart diseases, and it also has impact on the immune system. Thus, we sought to determine whether immunological activity would influence myocardial structure and function in elderly mice. Morphological, functional, and molecular analyses revealed that the age-related myocardial impairment occurs in parallel with shifts in the composition of tissueresident leukocytes and with an accumulation of activated CD4 + Foxp3 − (forkhead box P3) IFN-γ + T cells in the heart-draining lymph nodes. A comprehensive characterization of different aged immune-deficient mouse strains revealed that T cells significantly contribute to age-related myocardial inflammation and functional decline. Upon adoptive cell transfer, the T cells isolated from the mediastinal lymph node (med-LN) of aged animals exhibited increased cardiotropism, compared with cells purified from young donors or from other irrelevant sites. Nevertheless, these cells caused rather mild effects on cardiac functionality, indicating that myocardial aging might stem from a combination of intrinsic and extrinsic (immunological) factors. Taken together, the data herein presented indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.T he myocardial cellular composition has been revisited in recent years, and leukocyte subsets residing in the healthy heart have been described (1-10). Cardiac-resident macrophages exhibiting an M2-like gene expression profile were found to be distributed in close association with the coronary vascular bed (3), and niches for dendritic cells (CD11c + MHC-II high CD80/86 low ) were found near the cardiac valves of the intact heart (1). It was also demonstrated that cardiac-resident MHCII + cells process and present myosin heavy chain-alpha-derived peptides under steady-state conditions (11, 12) and prime T cells ex vivo (1). However, whether lymphocytes can seed the intact myocardium and whether T-cell priming with myocardial antigens can occur in the absence of an infection or autoimmune myocarditis remain elusive.More recently, accumulating evidence indicated that noninfectious myocardial diseases are modulated by T cells. During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13-16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20). However, these autoreactive T cells can also b...

The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy

“…Interestingly, our data show that pharmacological induction of AMPK that enhanced the autophagy improves contractile responses in aged murine cardiomyocytes challenged with LPS. A new published study showed that myocardial aging is a T-cell-mediated phenomenon that heart-directed immune responses may spontaneously arise in the elderly [23]. Improvement of LPS-induced mitochondrial dysfunction by fasudil was attributed to inhibition of ROCK-dependent Drp1 phosphorylation and activation of autophagic processes [24].…”

Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

“…1F), suggesting that chronic TLR2 deficiency causes contractile dysfunction in male mice. These overall changes closely resemble the cardiac structure and function of aged mice, which exhibited increased left ventricular dimension, decreased wall thickness, and decreased fractional shortening (34,35). To check whether the development of adverse remodelling and cardiac dysfunction is gender dependent, we analysed the cardiac structure and function of 8-month-old wild type and TLR2-KO female mice.…”

“…Age-dependent decline in the number of macrophages has been observed in aging hearts (35,43). Therefore, we tested whether TLR2-KO hearts showed any changes in the population of macrophages in the heart.…”

Immunotherapy for cardiovascular disease

“…Since the first description of inflammatory mediators in HF patients in 1990, the links between inflammation and HF have become an extensive subject of study. This applies to HF caused by different pathological conditions, ranging from ischemic injury, to pressure‐overload, or even low‐grade chronic stress . The details of what triggers the inflammatory response in HF are still not precisely deciphered, though among the possible causes one could list the mechanical stress that cardiomyocytes undergo during blood pressure overload, as well as the associated hypoxia and reactive oxygen species (ROS) generation; it is thought that this may induce the production of proinflammatory cytokines by the ailing myocardium .…”

“…This applies to HF caused by different pathological conditions, ranging from ischemic injury, 11 to pressure-overload, 12 or even low-grade chronic stress. 13 The details of what triggers the inflammatory response in HF are still not precisely deciphered, though among the possible causes one could list the mechanical stress that cardiomyocytes undergo during blood pressure overload, as well as the associated hypoxia and reactive oxygen species (ROS) generation; it is thought that this may induce the production of proinflammatory cytokines by the ailing myocardium. 9,14 The inflammatory response that occurs after cardiac injury is generally characterized by three phases: (1) production of inflammatory mediators (cytokines and chemokines), (2) recruitment of immune cells that intervene in the tissue remodeling process, (3) production of anti-inflammatory mediators that down-regulate the inflammatory response.…”