Senescence and Inflamm-Aging Are Associated With Endothelial Dysfunction in Men But Not Women With Atherosclerosis.

Coronary artery disease (CAD) is more prevalent in men than in women, with endothelial dysfunction, prodromal to CAD, developing a decade earlier in middle-aged men. We investigated the molecular basis of this dimorphism ex vivo in arterial segments discarded during surgery of CAD patients. The results reveal a lower endothelial relaxant sensitivity in men, and a senescence-associated inflammaging transcriptomic signature in endothelial cells.

Effects of variation in exercise training load on cognitive performances and neurotrophic biomarkers in patients with coronary artery disease.

This study compared the effects of linear (LP) and nonlinear (NLP) training periodization on cognitive functions, neurotrophic biomarkers [plasma brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1)], and cathepsin-B in patients with coronary artery disease (CAD). Forty-four patients with CAD reported to our laboratory on two occasions to undergo testing procedures before and after training sessions, and were then blindly randomized to NLP or LP for 36 training sessions. included blood samples and a maximal cardiopulmonary exercise testing to get maximal oxygen uptake (V̇o).

Knockdown of ANGPTL2 promotes left ventricular systolic dysfunction by upregulation of NOX4 in mice.

Angiopoietin-like 2 (ANGPTL2) is a pro-inflammatory and pro-oxidant circulating protein that predicts and promotes chronic inflammatory diseases such as atherosclerosis in humans. Transgenic murine models demonstrated the deleterious role of ANGPTL2 in vascular diseases, while deletion of ANGPTL2 was protective. The nature of its role in cardiac tissues is, however, less clear.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

Aims: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF.

NTPDase1/CD39 Ectonucleotidase Is Necessary for Normal Arterial Diameter Adaptation to Flow.

NTPDase1/CD39, the major vascular ectonucleotidase, exerts thrombo-immunoregulatory function by controlling endothelial P2 receptor activation. Despite the well-described release of ATP from endothelial cells, few data are available regarding the potential role of CD39 as a regulator of arterial diameter. We thus investigated the contribution of CD39 in short-term diameter adaptation and long-term arterial remodeling in response to flow using male mice.

Angiopoietin-Like Proteins: Cardiovascular Biology and Therapeutic Targeting for the Prevention of Cardiovascular Diseases.

Despite the best pharmacologic tools available, cardiovascular diseases (CVDs) remain a major cause of morbidity and mortality in developed countries. After 2 decades of research, new therapeutic targets, such as angiopoietin-like proteins (ANGPTLs), are emerging. ANGPTLs belong to a family of 8 members, from ANGPTL1 to ANGPTL8; they have structural homology with angiopoietins and are secreted in the circulation.

Increased serum S100A12 levels are associated with higher risk of acute heart failure in patients with type 2 diabetes.

Aims: The hyperglycaemic stress induces the release of inflammatory proteins such as S100A12, one of the endogenous ligands of the receptors for advanced glycation end products (RAGE). Chronic activation of RAGE has multiple deleterious effects in target tissues such as the heart and the vessels by promoting oxidative stress, inflammation by the release of cytokines, macrophages infiltration, and vascular cell migration and proliferation, causing ultimately endothelial cell and cardiomyocyte dysfunction. The aim of our study was to investigate the prognostic value of circulating S100A12 beyond established cardiovascular risk factors (CVRF) for heart failure (HF) and major adverse cardiovascular events (MACE) in a cohort of patients with type 2 diabetes.

Angiopoietin-like 2 is essential to aortic valve development in mice.

Aortic valve (AoV) abnormalities during embryogenesis are a major risk for the development of aortic valve stenosis (AVS) and cardiac events later in life. Here, we identify an unexpected role for Angiopoietin-like 2 (ANGPTL2), a pro-inflammatory protein secreted by senescent cells, in valvulogenesis. At late embryonic stage, mice knocked-down for Angptl2 (Angptl2-KD) exhibit a premature thickening of AoV leaflets associated with a dysregulation of the fine balance between cell apoptosis, senescence and proliferation during AoV remodeling and a decrease in the crucial Notch signalling.

Differences in cognitive function, cardiorespiratory fitness and BDNF concentration in physically active CHD patients vs healthy controls.

Background: Coronary heart disease (CHD) is frequently associated with cognitive impairment (CI), whereas physical exercise may improve cognition. To date, the cognitive profile of physically active CHD patients remains poorly understood. Physical activity and cognition has been associated with neurotrophic biomarkers that are positively modulated by a higher cardiorespiratory fitness (V̇ Opeak) and/or active lifestyle.

Adenylate cyclase type 9 antagonizes cAMP accumulation and regulates endothelial signalling involved in atheroprotection.

Aims: The adenylate cyclase type 9 (ADCY9) gene appears to determine atherosclerotic outcomes in patients treated with dalcetrapib. In mice, we recently demonstrated that Adcy9 inactivation potentiates endothelial function and inhibits atherogenesis. The objective of this study was to characterize the contribution of ADCY9 to the regulation of endothelial signalling pathways involved in atherosclerosis.

Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence.

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP).

Design of a Randomized Placebo-Controlled Trial to Evaluate the Anti-inflammatory and Senolytic Effects of Quercetin in Patients Undergoing Coronary Artery Bypass Graft Surgery.

Following an acute coronary syndrome, patients display an elevated inflammatory profile, promoted in part by cellular senescence. For patients requiring a coronary artery bypass (CABG) surgery, exposure to the surgical intervention and cardiopulmonary bypass further exacerbate their residual inflammation. Experimental evidence identified quercetin, a natural senolytic drug, as a cardioprotective agent against inflammatory injuries.

The role of cellular senescence in cardiac disease: basic biology and clinical relevance.

Cellular senescence, classically defined as stable cell cycle arrest, is implicated in biological processes such as embryogenesis, wound healing and ageing. Senescent cells have a complex senescence-associated secretory phenotype (SASP), involving a range of pro-inflammatory factors with important paracrine and autocrine effects on cell and tissue biology. Clinical evidence and experimental studies link cellular senescence, senescent cell accumulation, and the production and release of SASP components with age-related cardiac pathologies such as heart failure, myocardial ischaemia and infarction, and cancer chemotherapy-related cardiotoxicity.

Therapeutic Potential of Quercetin to Alleviate Endothelial Dysfunction in Age-Related Cardiovascular Diseases.

The vascular endothelium occupies a catalog of functions that contribute to the homeostasis of the cardiovascular system. It is a physically active barrier between circulating blood and tissue, a regulator of the vascular tone, a biochemical processor and a modulator of coagulation, inflammation, and immunity. Given these essential roles, it comes to no surprise that endothelial dysfunction is prodromal to chronic age-related diseases of the heart and arteries, globally termed cardiovascular diseases (CVD).

Pathological Continuum From the Rise in Pulse Pressure to Impaired Neurovascular Coupling and Cognitive Decline.

The "biomechanical hypothesis" stipulates that with aging, the cumulative mechanical damages to the cerebral microvasculature, magnified by risk factors for vascular diseases, contribute to a breach in cerebral homeostasis producing neuronal losses. In other words, vascular dysfunction affects brain structure and function, and leads to cognitive failure. This is gathered under the term Vascular Cognitive Impairment and Dementia (VCID).

Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort.

Aims/hypothesis: Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.

A Pilot Study Investigating Changes in Capillary Hemodynamics and Its Modulation by Exercise in the APP-PS1 Alzheimer Mouse Model.

Dysfunction in neurovascular coupling that results in a mismatch between cerebral blood flow and neuronal activity has been suggested to play a key role in the pathogenesis of Alzheimer's disease (AD). Meanwhile, physical exercise is a powerful approach for maintaining cognitive health and could play a preventive role against the progression of AD. Given the fundamental role of capillaries in oxygen transport to tissue, our pilot study aimed to characterize changes in capillary hemodynamics with AD and AD supplemented by exercise.

Voluntary exercise increases brain tissue oxygenation and spatially homogenizes oxygen delivery in a mouse model of Alzheimer's disease.

Although vascular contributions to dementia and Alzheimer's disease (AD) are increasingly recognized, the potential brain oxygenation disruption associated with AD and whether preventive strategies to maintain tissue oxygenation are beneficial remain largely unknown. This study aimed to examine (1) whether brain oxygenation is compromised by the onset of AD and (2) how voluntary exercise modulates the influence of AD on brain oxygenation. In vivo 2-photon phosphorescence lifetime microscopy was used to investigate local changes of brain tissue oxygenation with the progression of AD and its modulation by exercise in the barrel cortex of awake transgenic AD mice.

Hypertension accelerates cerebral tissue PO disruption in Alzheimer's disease.

This study measured stimulus-evoked brain tissue oxygenation changes in a mouse model of Alzheimer disease (AD) and further explored the influence of exercise and angiotensin II-induced hypertension on these changes. in vivo two-photon phosphorescence lifetime microscopy was used to investigate local changes in brain tissue oxygenation following whisker stimulation. During rest periods, PO values close to the arteriolar wall were lower in the AD groups and the PO spatial decay as a function of distance to arteriole was increased by hypertension.

Therapeutic Targeting of LRP6 in Cardiovascular Diseases: Challenging But Not Wnt-Possible!

Coronary artery disease (CAD), often related to dyslipidemia, is a major cause of death worldwide, highlighting unmet therapeutic needs. Lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptor (LDLR) family composed of structurally related cell surface receptors and acts, in consort with Frizzled receptors, as a coreceptor to mediate the Wnt/β-catenin signalling pathway. Impaired LRP6 signalling in humans has been associated with multiple cardiovascular risk factors such as elevated serum LDL, triglycerides, and glucose levels.

Impact of atherosclerotic disease on cerebral microvasculature and tissue oxygenation in awake LDLR-/-hApoB+/+ transgenic mice.

We explore cortical microvasculature changes during the progression of atherosclerosis using young and old transgenic atherosclerotic (ATX) mice with thinned-skull cranial window. In awake animals, exploiting intrinsic signal optical imaging, Doppler optical coherence tomography, and two-photon microscopy, we investigate how the progression of atherosclerotic disease affects the morphology and function of cortical microvasculature as well as baseline cerebral tissue oxygenation. Results show that aged ATX mice exhibited weaker hemodynamic response in the somatosensory cortex to whisker stimulation and that the diameter of their descending arterioles and associated mean blood flow decreased significantly compared with the young ATX group.