Quercetin and dasatinib, two powerful senolytics in age-related cardiovascular disease.

Cellular senescence is characteristic of the development and progression of multiple age-associated diseases. Accumulation of senescent cells in the heart contributes to various age-related pathologies. Several compounds called senolytics have been designed to eliminate these cells within the tissues. In recent years, the use and study of senolytics increased, representing a promising field for finding accessible and safe therapies for cardiovascular disease (CVD) treatment. This mini-review discusses the changes in the aging heart and the participation of senescent cells in CVD, as well as the use of senolytics to prevent the progression of myocardial damage, mainly the effect of dasatinib and quercetin. In particular, the mechanisms and physiological effects of senolytics therapies in the aged heart are discussed.

Iron status and oxidative stress in the aged rabbit heart.

Altered iron status may be relevant to the pathophysiology of aging. We have assessed redox-active catalytic low molecular weight iron (LMWI), non-heme iron (NHI), heme iron (HI), and total iron (TI) in the aerobically perfused hearts of aged rabbits (AR, about 4.5years old) and young adult control rabbits (YACR, 3-4months old); myocardial lipid and protein oxidations were also assessed as oxidative stress biomarkers. The levels of LMWI and NHI, as well as of lipid and protein oxidation, were higher, while HI content was lower, in the hearts of AR than in those of YACR; TI did not differ significantly between the two groups. Together with these findings, hemodynamic dysfunction, namely heightened end-diastolic pressure (EDP) and lowered coronary flow (CF), occurred in the AR hearts. Notably, such pattern of hemodynamic dysfunction associated with myocardial oxidant damage occurred in the hearts of other YACR perfused in the presence of a cell-permeable form of iron, i.e., the iron/hydroxyquinoline complex, pointing to the involvement of catalytic iron in the aged heart damage. Moreover, as shown in other AR, heart perfusion in the presence of the iron chelator deferoxamine (0.6mM or 3.6mM) reduced the myocardial levels of LMWI, without significantly affecting those of NHI, HI, and TI; concomitantly, in AR deferoxamine lowered myocardial lipid and protein oxidation, and reduced EDP with a tendency to augment CF. Instead, deferoxamine, even at high concentration of 3.6mM, had no significant effects in the YACR. In conclusion, altered iron status with catalytic LMWI burden occurs in the aged rabbit heart, eventually resulting in iron-dependent cardiac oxidative stress and hemodynamic dysfunction.

NOX Inhibition Improves ß-Adrenergic Stimulated Contractility and Intracellular Calcium Handling in the Aged Rat Heart.

Cardiac aging is characterized by alterations in contractility and intracellular calcium ([Ca2+]i) homeostasis. It has been suggested that oxidative stress may be involved in this process. We and others have reported that in cardiomyopathies the NADPH oxidase (NOX)-derived superoxide is increased, with a negative impact on [Ca2+]i and contractility. We tested the hypothesis that in the aged heart, [Ca2+]i handling and contractility are disturbed by NOX-derived superoxide. For this we used adults (≈5 month-old) and aged (20⁻24 month-old) rats. Contractility was evaluated in isolated hearts, challenged with isoproterenol. To assess [Ca2+]i, isolated cardiac myocytes were field-stimulated and [Ca2+]i was monitored with fura-2. Cardiac concentration-response to isoproterenol was depressed in aged compared to adults hearts (p < 0.005), but was restored by NOX inhibitors apocynin and VAS2870. In isolated cardiomyocytes, apocynin increased the amplitude of [Ca2+]i in aged myocytes (p < 0.05). Time-50 [Ca2+]i decay was increased in aged myocytes (p < 0.05) and reduced towards normal by NOX inhibition. In addition, we found that myofilaments Ca2+ sensitivity was reduced in aged myocytes (p < 0.05), and was further reduced by apocynin. NOX2 expression along with NADPH oxidase activity was increased in aged hearts. Phospholamban phosphorylation (Ser16/Thr17) after isoproterenol treatment was reduced in aged hearts compared to adults and was restored by apocynin treatment (p < 0.05). In conclusion, ß-adrenergic-induced contractility was depressed in aged hearts, and NOX inhibition restored back to normal. Moreover, altered Ca2+ handling in aged myocytes was also improved by NOX inhibition. These results suggest a NOX-dependent effect in aged myocytes at the level of Ca2+ handling proteins and myofilaments.

Protecting the aged heart during cardiac surgery: single-dose del Nido cardioplegia is superior to multi-dose del Nido cardioplegia in isolated rat hearts.

BACKGROUND: Aged hearts are particularly vulnerable to reperfusion injury. We recently showed that single-dose del Nido cardioplegia was superior to 'standard' multi-dose 4:1 blood cardioplegia in aged rat hearts. This study seeks to determine if multi-dose del Nido cardioplegia offers additional benefits over single-dose del Nido cardioplegia. METHODS: Functional recovery after 60 min of cardioplegic arrest was assessed in isolated, working, senescent rat hearts. Single-dose del Nido cardioplegia (n=14) was compared to multi-dose del Nido cardioplegia (n=12) delivered every 20 min. RESULTS: Troponin release during reperfusion was similar in the single (0.263 ± 0.056 ng/ml) and multi-dose groups (0.261 ± 0.055 ng/ml). Although functional recovery was similar early after reperfusion (stroke work 91 ± 6 ml*mmHg*g(-1) vs. 91 ± 8 ml*mmHg*g(-1) for single- vs. multi-dose), it declined over time in the multi-dose group (71 ± 9 vs. 43 ± 9 ml*mmHg*g(-1) at 60 min, p=0.0175) CONCLUSIONS: In aged rat hearts, a single-dose del Nido cardioplegia strategy results in superior functional recovery compared to a multi-dose del Nido cardioplegia strategy.

The Role of Oxidative Stress in the Aging Heart.

Medical advances and the availability of diagnostic tools have considerably increased life expectancy and, consequently, the elderly segment of the world population. As age is a major risk factor in cardiovascular disease (CVD), it is critical to understand the changes in cardiac structure and function during the aging process. The phenotypes and molecular mechanisms of cardiac aging include several factors. An increase in oxidative stress is a major player in cardiac aging. Reactive oxygen species (ROS) production is an important mechanism for maintaining physiological processes; its generation is regulated by a system of antioxidant enzymes. Oxidative stress occurs from an imbalance between ROS production and antioxidant defenses resulting in the accumulation of free radicals. In the heart, ROS activate signaling pathways involved in myocyte hypertrophy, interstitial fibrosis, contractile dysfunction, and inflammation thereby affecting cell structure and function, and contributing to cardiac damage and remodeling. In this manuscript, we review recent published research on cardiac aging. We summarize the aging heart biology, highlighting key molecular pathways and cellular processes that underlie the redox signaling changes during aging. Main ROS sources, antioxidant defenses, and the role of dysfunctional mitochondria in the aging heart are addressed. As metabolism changes contribute to cardiac aging, we also comment on the most prevalent metabolic alterations. This review will help us to understand the mechanisms involved in the heart aging process and will provide a background for attractive molecular targets to prevent age-driven pathology of the heart. A greater understanding of the processes involved in cardiac aging may facilitate our ability to mitigate the escalating burden of CVD in older individuals and promote healthy cardiac aging.

Evidence for oxidative and not reductive stress in the aged rabbit heart.

Reductive stress, which is due to a paradoxical excess of antioxidants such as reduced glutathione (GSH) and GSH-related enzymes associated with decreased oxidant levels, has emerged as a pathogenetic mechanism of myocardial damage in pathological conditions such as protein aggregation cardiomyopathy. Notably, in the aged heart a cardiomyopathy-like pathology occurs leading to myocardial dysfunction. Whether reductive stress, or instead its counterpart oxidative stress, is operative in the aged mammalian heart needs to be elucidated also for the different therapeutic implications of such redox stress conditions. In the present investigation, we assessed GSH and the specific enzymatic activities of γ-glutamylcysteine synthetase (γ-GCS), glutathione reductase (GSSG-Red) and selenium-dependent glutathione peroxidase (GSH-Px) as endogenous antioxidants, together with oxidized glutathione (GSSG) and the glutathione redox ratio (GSH/GSSG), in the aerobically perfused hearts of aged rabbits (about 4.5 years old) and young adult control rabbits (3-4 months old). We also assessed in the aged and control hearts H2O2 and catalytically active low molecular weight iron (LMWI) as oxidant forces, as well as fluorescent damage products of lipid peroxidation (FDPL) and protein carbonyls (PC) as biomarkers of lipid and protein oxidation. Moreover, the effects of 4.5 mM N-acetylcysteine (NAC) as reducing thiol antioxidant were studied on hemodynamic parameters and lipid peroxidation in the perfused hearts of the aged and control rabbits. The levels of GSH and of the GSH/GSSG ratio were lower, and those of GSSG higher, in the aged than in the control hearts. The aged hearts were also characterized by decreased activities of the antioxidant enzymes γ-GCS, GSSG-Red and GSH-Px, as well as by heightened levels of H2O2, LMWI, FDPL and PC, highlighting the occurrence of aging-dependent oxidative stress. Associated with such biochemical alterations, hemodynamic dysfunction occurred in the aged rabbit hearts, as evidenced by lowered developed pressure (DP) and enhanced end-diastolic pressure (EDP) with decreased coronary flow (CF). Remarkably, NAC administration significantly improved DP and EDP, and lowered lipid peroxidation, electively in the aged hearts. In conclusion, oxidative and not reductive stress is operative in the aged rabbit heart, whose hemodynamic dysfunction is improved by NAC together with reduction in myocardial lipid peroxidation.

Involvement of exogenous H2S in recovery of cardioprotection from ischemic post-conditioning via increase of autophagy in the aged hearts.

BACKGROUND: Hydrogen sulfide (H2S), which is a member of the gasotransmitter family, plays an important physiological and pathological role in cardiovascular system. Ischemic post-conditioning (PC) provides myocardial protective effect in the young hearts but not in the aged hearts. Exogenous H2S restores PC-induced cardioprotection by inhibition of mitochondrial permeability transition pore (mPTP) in the aged hearts. However, whether H2S contributes to the recovery of PC-induced cardioprotection via up-regulation of autophagy in the aged hearts is unclear. METHODS: The isolated aged rat hearts (24-months-old, 450-500g) and aged cardiomyocytes-induced by d-galactose were exposed to an ischemia/reperfusion (I/R) and PC protocol. RESULTS: We found PC lost cardioprotection in the aged hearts and cardiomyocytes. NaHS (a H2S donor) significantly restored cardioprotection of PC through decreasing myocardial damage, infarct size, and apoptosis, improving cardiac function, increasing cell viability and autophagy in the aged hearts and cardiomyocytes. 3-MA (an autophagy inhibitor) abolished beneficial effect of NaHS in the aged hearts. In addition, in the aged cardiomyocytes, NaHS up-regulated AMPK/mTOR pathway, and the effect of NaHS on PC was similar to the overexpression of Atg 5, treatment of AICAR (an AMPK activator) or Rapamycin (a mTOR inhibitor, an autophagy activator), respectively. CONCLUSIONS: These results suggest that exogenous H2S restores cardioprotection from PC by up-regulation of autophagy via activation of AMPK/mTOR pathway in the aged hearts and cardiomyocytes.

Análise dos Índices Espectrais da Variabilidade da Frequência Cardíaca Durante a Mudança Postural de Idosos Hipertensos / Analysis of Spectral Indexes of Variability of Cardiac Frequency during the Postural Change of Hypertensive Elderly

O estudo da Variabilidade da Frequência Cardíaca (VFC) tem permitido, de forma não invasiva, avaliar o Sistema Nervoso autônomo e o risco cardíaco, sendo um importante indicador prognóstico de doenças cardíacas e sistêmicas. O objetivo foi avaliar e comparar a VFC no domínio da frequência e do tempo de idosos com hipertensão arterial e de idosos saudáveis frente à mudança postural de repouso para sentado. Foram estudados 18 indivíduos hipertensos e 18 indivíduos saudáveis na faixa etária de 60 a 85 anos. A frequência cardíaca e os intervalos R-R foram coletados pelo instrumento Polar S810i durante 1200 s nas posturas supina e sentada. A VFC foi analisada no domínio do tempo - DT pelas variáveis: Índice raiz quadrada da média dos quadrados das diferenças entre intervalos R-R (iR-R) sucessivos (RMSSD), desvio padrão da média dos iR-R normais em ms - SDNN e PNN50%, que traduz a diferença de duração superior a 50 milissegundos, e no domínio da frequência, pelas bandas de alta (AF) e baixa frequência (BF), e da razão BF/AF. Ocorreu alteração na VFC dos idosos tanto no grupo controle e hipertenso, no entanto não houve mudanças significativas na VFC entre os grupos estudados. Ao analisar a VFC no domínio do tempo, o estudo mostrou que a amostragem estudada apresenta alto risco cardíaco ao analisar o parâmetro SDNN. Conclui-se que a mudança postural alterou a VFC desses idosos, tanto no grupo controle e hipertenso, no entanto não houve mudanças significativas na VFC entre as fases dos grupos estudados e obteve-se como resultado alto risco cardíaco ao avaliar o parâmetro SDNN em ambos os grupos. (AU).

The study of heart rate variability (HRV) allows noninvasive way to evaluate the autonomic nervous system and cardiac risk, and an important prognostic indicator of heart and systemic diseases disease. The objective was to evaluate and compare the HRV in the frequency and duration of elderly patients with hypertension and healthy elderly versus postural change in the condition of rest. The study comprised 18 hypertensive individuals and 18 healthy subjects aged 60 to 85 years, both sexes. Heart rate and RR intervals were collected by the instrument Polar S810i during 1200 s in supine and sitting postures. HRV was analyzed in time domain indices SDNN, RMSSD and PNN50% and the frequency domain, by bands of high (AF) and low frequency (LF), and the ratio LF / HF. Intergroup intra-analyes were used as well as the tests of normality D'Augustine as a criterion for parametric groups. There was change in heart rate variability of both the elderly and hypertensive patients in the control group, however there were no significant changes in studied HRV intergroups . In the area of the time it was found that the sampling shows high-risk cardiac parsing the parameter SDNN. The results showed that the change posture changed the variability of heart rate in the control group and hypertension, however there were no significant changes in HRV among the phases of the groups and a high risk was obtained as a result of the parameter SDNN for both heart the groups. (AU).