Abstract “Inside every old person is a young person wondering what happened.” So, what is aging? Aging is a manifestation of progressive, time-dependent failure of molecular mechanisms that create ...disorder within a system of DNA and its environment (nuclear, cytosolic, tissue, organ, organism, other organisms, society, terra firma, atmosphere, universe). Continuous signaling, transmitted with different kinetics across each of these environments, confers a “mutual enslavement” that creates ordered functions among the components within the system. Accrual of this molecular disorder over time, i.e. during aging, causes progressive changes in the structure and function of the heart and arteries that are quite similar in humans, non-human primates, rabbits and rats that compromise cardiovascular reserve function, and confer a marked risk for incident cardiovascular disease. Nearly all aspects of signaling within the DNA environment system within the heart and arteries become disordered with advancing age: Signals change, as does sensing of the signals, transmission of signals and responses to signals, impaired cell renewal, changes in the proteome due to alterations in genomic transcription, mRNA translation, and proteostasis. The density of some molecules becomes reduced, and post-translational modifications, e.g. oxidation and nitration phosphorylation, lead to altered misfolding and disordered molecular interactions. The stoichiometry and kinetics of enzymatic and those reactions which underlie crucial cardiac and vascular cell functions and robust reserve mechanisms that remove damaged organelles and proteins deteriorate. The CV cells generate an inflammatory defense in an attempt to limit the molecular disorder. The resultant proinflammatory milieu is not executed by “professional” inflammatory cells (i.e. white blood cells), however, but by activation of renin–angiotensin–aldosterone endothelin signaling cascades that leads to endothelial and vascular smooth muscle and cardiac cells' phenotype shifts, resulting in production of inflammatory cytokines. Progressive molecular disorder within the heart and arteries over time leads to an excessive allostatic load on the CV system, that results in an increase and “overshoot” in the inflammatory defense signaling. This age-associated molecular disorder-induced inflammation that accrues in the heart and arteries does not, itself, cause clinical signs or symptoms of CVD. Clinical signs and symptoms of these CVDs begin to emerge, however, when the age-associated inflammation in the heart and arteries exceeds a threshold. Thus, an emerging school of thought is that accelerated age-associated alterations within the heart and arteries, per se, ought to be considered to be a type of CVD, because the molecular disorder and the inflammatory milieu it creates within the heart and arteries with advancing age are the roots of the pathophysiology of most cardiovascular diseases, e.g. athersclerosis and hypertension. Because many effects of aging on the CV system can be delayed or attenuated by changes in lifestyle, e.g. diet and exercise, or by presently available drugs, e.g. those that suppress Ang II signaling, CV aging is a promising frontier in preventive cardiology that is not only ripe for, but also in dire need of attention! There is an urgency to incorporate the concept of cardiovascular aging as a disease into clinical medicine. But, sadly, the reality of the age-associated molecular disorder within the heart and ateries has, for the most part, been kept outside of mainstream clinical medicine. This article is part of a Special Issue entitled CV Aging.
Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under ...voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface “membrane clock” (M clock). Localized subsarcolemmal Ca releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular “Ca clock,” because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca, and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein–coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs.
Biological rhythms exist in organisms at all levels of complexity, in most organs and at myriad time scales. Our own biological rhythms are driven by energy emitted by the sun, interacting via our ...retinas with brain stem centres, which then send out complex messages designed to synchronize the behaviour of peripheral non-light sensing organs, to ensure optimal physiological responsiveness and performance of the organism based on the time of day. Peripheral organs themselves have autonomous rhythmic behaviours that can act independently from central nervous system control but is entrainable. Dysregulation of biological rhythms either through environment or disease has far-reaching consequences on health that we are only now beginning to appreciate. In this review, we focus on cardiovascular rhythms in health, with ageing and under disease conditions.
Central arterial wall stiffening, driven by a chronic inflammatory milieu, accompanies arterial diseases, the leading cause of cardiovascular (CV) morbidity and mortality in Western society. An ...increase in central arterial wall stiffening, measured as an increase in aortic pulse wave velocity (PWV), is a major risk factor for clinical CV disease events. However, no specific therapies to reduce PWV are presently available. In rhesus monkeys, a 2 year diet high in fat and sucrose (HFS) increases not only body weight and cholesterol, but also induces prominent central arterial wall stiffening and increases PWV and inflammation. The observed loss of endothelial cell integrity, lipid and macrophage infiltration, and calcification of the arterial wall were driven by genomic and proteomic signatures of oxidative stress and inflammation. Resveratrol prevented the HFS-induced arterial wall inflammation and the accompanying increase in PWV. Dietary resveratrol may hold promise as a therapy to ameliorate increases in PWV.
Display omitted
•Resveratrol supplementation prevented diet-induced increase in arterial stiffness•Resveratrol reduced macrophage infiltration, lipid deposition, and calcification•Gene expression changes indicate antioxidative and antiinflammatory effects•Primary culture of vascular smooth muscle cells support a role of resveratrol
Using a monkey model of diet-induced obesity, Mattison et al. show that dietary supplementation of resveratrol for 2 years dampens oxidative stress and inflammation, which improves vascular function and decreases arterial wall stiffening, a major risk factor for cardiovascular diseases.
Proinflammation: the key to arterial aging Wang, Mingyi; Jiang, Liqun; Monticone, Robert E ...
Trends in endocrinology and metabolism,
02/2014, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Highlights • Arterial aging causes chronic arterial inflammation. • Age-associated arterial wall chronic inflammation drives arterial cell phenotypic shifts and adverse arterial wall remodeling. • ...The inflamed arterial wall in advancing age confers the major risk for hypertension and atherosclerosis. • Interventions to suppress chronic arterial inflammation may beneficially impact age-associated arterial diseases in our society.
RATIONALE:Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac ...function remains poorly understood.
OBJECTIVE:To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction.
METHODS AND RESULTS:Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death.
CONCLUSIONS:These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.
PDF
