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Despite remarkable advances in therapy, heart failure remains a leading cause of morbidity and mortality. Although enhanced beta-adrenergic receptor stimulation is part of normal physiologic adaptation to either the increase in physiologic demand or decrease in cardiac function, chronic beta-adrenergic stimulation has been associated with increased mortality and morbidity in both animal models and humans. For example, overexpression of cardiac Gsalpha or beta-adrenergic receptors in transgenic mice results in enhanced cardiac function in young animals, but with prolonged overstimulation of this pathway, cardiomyopathy develops in these mice as they age. Similarly, chronic sympathomimetic amine therapy increases morbidity and mortality in patients with heart failure. Conversely, the use of beta-blockade has proven to be of benefit and is currently part of the standard of care for heart failure. It is conceivable that interrupting distal mechanisms in the beta-adrenergic receptor-G protein-adenylyl cyclase pathway may also provide targets for future therapeutic modalities for heart failure. Interestingly, there are two major isoforms of adenylyl cyclase (AC) in the heart (type 5 and type 6), which may exert opposite effects on the heart, i.e., cardiac overexpression of AC6 appears to be protective, whereas disruption of type 5 AC prolongs longevity and protects against cardiac stress. The goal of this review is to summarize the paradigm shift in the treatment of heart failure over the past 50 years from administering sympathomimetic amine agonists to administering beta-adrenergic receptor antagonists, and to explore the basis for a novel therapy of inhibiting type 5 AC. [ABSTRACT FROM AUTHOR]

There are two major subtypes of adipose tissue, i.e., white adipose tissue (WAT) and brown adipose tissue (BAT). It has been known for a long time that WAT mediates obesity and impairs healthful longevity. More recently, interest has focused on BAT, which, unlike WAT, actually augments healthful aging. The goal of this review is to examine the role of BAT in mediating healthful longevity. A major role for BAT and its related beige adipose tissue is thermogenesis, as a mechanism to maintain body temperature by producing heat through uncoupling protein 1 (UCP1) or through UCP1-independent thermogenic pathways. Our hypothesis is that healthful longevity is, in part, mediated by BAT. BAT protects against the major causes of impaired healthful longevity, i.e., obesity, diabetes, cardiovascular disorders, cancer, Alzheimer's disease, reduced exercise tolerance, and impaired blood flow. Several genetically engineered mouse models have shown that BAT enhances healthful aging and that their BAT is more potent than wild-type (WT) BAT. For example, when BAT, which increases longevity and exercise performance in mice with disruption of the regulator of G protein signaling 14 (RGS14), is transplanted to WT mice, their exercise capacity is enhanced at 3 days after BAT transplantation, whereas BAT transplantation from WT to WT mice also resulted in increased exercise performance, but only at 8 weeks after transplantation. In view of the ability of BAT to mediate healthful longevity, it is likely that a pharmaceutical analog of BAT will become a novel therapeutic modality., Competing Interests: Conflicts of interest All authors declared that there are no conflicts of interest.

Purpose: We investigated the effects of gut microbes, and the mechanisms mediating the enhanced exercise performance induced by exercise training, i.e., skeletal muscle blood flow, and mitochondrial biogenesis and oxidative function in male mice., Methods: All mice received a graded exercise test before (PRE) and after exercise training via forced treadmill running at 60% to 70% of maximal running capacity 5 d·wk -1 for 5 wk (POST). To examine the role of the gut microbes, the graded exercise was repeated after 7 d of access to antibiotic (ABX)-treated water, used to eliminate gut microbes. Peripheral blood flow, mitochondrial oxidative capacity, and markers of mitochondrial biogenesis were collected at each time point., Results: Exercise training led to increases of 60% ± 13% in maximal running distance and 63% ± 11% work to exhaustion ( P < 0.001). These increases were abolished after ABX ( P < 0.001). Exercise training increased hindlimb blood flow and markers of mitochondrial biogenesis and oxidative function, including AMP-activated protein kinase, sirtuin-1, PGC-1α citrate synthase, complex IV, and nitric oxide, all of which were also abolished by ABX treatment., Conclusions: Our results support the concept that gut microbiota mediate enhanced exercise capacity after exercise training and the mechanisms responsible, i.e., hindlimb blood flow, mitochondrial biogenesis, and metabolic profile. Finally, results of this study emphasize the need to fully examine the impact of prescribing ABX to athletes during their training regimens and how this may affect their performance., (Copyright © 2023 by the American College of Sports Medicine.)

Enhanced exercise capacity is not only a feature of healthful aging, but also a therapy for aging patients and patients with cardiovascular disease. Disruption of the Regulator of G Protein Signaling 14 (RGS14) in mice extends healthful lifespan, mediated by increased brown adipose tissue (BAT). Accordingly, we determined whether RGS14 knockout (KO) mice exhibit enhanced exercise capacity and the role of BAT in mediating exercise capacity. Exercise was performed on a treadmill and exercise capacity was assessed by maximal running distance and work to exhaustion. Exercise capacity was measured in RGS14 KO mice and their wild types (WT), and also in WT mice with BAT transplantation from RGS14 KO mice or from other WT mice. RGS14 KO mice demonstrated 160 ± 9% increased maximal running distance and 154 ± 6% increased work to exhaustion, compared to WT mice. RGS14 KO BAT transplantation to WT mice, resulted in a reversal of phenotype, with the WT mice receiving the BAT transplant from RGS14 KO mice demonstrating 151 ± 5% increased maximal running distance and 158 ± 7% increased work to exhaustion, at three days after BAT transplantation, compared to RGS14 KO donors. BAT transplantation from WT to WT mice also resulted in increased exercise performance, but not at 3 days, but only at 8 weeks after transplantation. The BAT induced enhanced exercise capacity was mediated by (1) mitochondrial biogenesis and SIRT3; (2) antioxidant defense and the MEK/ERK pathway, and increased hindlimb perfusion. Thus, BAT mediates enhanced exercise capacity, a mechanism more powerful with RGS14 disruption., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The goal of this review is to provide further understanding of increased vascular stiffness with aging, and how it contributes to the adverse effects of major human diseases. Differences in stiffness down the aortic tree are discussed, a topic requiring further research, because most prior work only examined one location in the aorta. It is also important to understand the divergent effects of increased aortic stiffness between males and females, principally due to the protective role of female sex hormones prior to menopause. Another goal is to review human and non-human primate data and contrast them with data in rodents. This is particularly important for understanding sex differences in vascular stiffness with aging as well as the changes in vascular stiffness before and after menopause in females, as this is controversial. This area of research necessitates studies in humans and non-human primates, since rodents do not go through menopause. The most important mechanism studied as a cause of age-related increases in vascular stiffness is an alteration in the vascular extracellular matrix resulting from an increase in collagen and decrease in elastin. However, there are other mechanisms mediating increased vascular stiffness, such as collagen and elastin disarray, calcium deposition, endothelial dysfunction, and the number of vascular smooth muscle cells (VSMCs). Populations with increased longevity, who live in areas called "Blue Zones," are also discussed as they provide additional insights into mechanisms that protect against age-related increases in vascular stiffness. Such increases in vascular stiffness are important in mediating the adverse effects of major cardiovascular diseases, including atherosclerosis, hypertension and diabetes, but require further research into their mechanisms and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vatner, Zhang, Vyzas, Mishra, Graham and Vatner.)

Most studies on ischemic preconditioning (IPC) use one or two ischemic stimuli before examining cardioprotection. To better simulate the clinical situation, we examined, in pigs, the effects of six episodes of 10 min coronary artery occlusion (CAO) 12 h apart, followed by 60 min CAO. We named this model the fourth window of IPC. To determine the novel mechanisms mediating cardioprotection in the fourth window, gene analysis was examined in fourth window IPC cardiac tissue 60 min after the last episode of 10 min CAO. Secreted frizzled-related protein 3 ( sFRP3 ) was the most significantly upregulated gene that was unique to the fourth window, that is, not found in the first, second, or third window IPC. To study the effects of sFRP3 on cardioprotection, sFRP3 was injected in the hearts of wild-type (WT) mice. In the [CAO/coronary artery reperfusion (CAR)] model (30 min CAO followed by 24 h CAR), infarct size was less, P < 0.01, after sFRP3 injection (14% ± 1.7%) compared with vehicle injection (48% ± 1.6%). sFRP3 injection also protected the development of heart failure following permanent CAO for 2 wk. Left ventricular ejection fraction was significantly improved, P < 0.05, at 2 wk after CAO with sFRP3 (53% ± 5%) compared with vehicle (36% ± 2%) and was accompanied by significant, P < 0.01, reductions in myocardial fibrosis (53% ± 4%), myocyte size (17% ± 3%), apoptosis (100%), and mortality (56%). Thus, sFRP3 , unique to the clinically relevant fourth window IPC model, is a novel mechanism mediating ischemic cardioprotection. NEW & NOTEWORTHY 1 ) This investigation identifies the novel fourth window of ischemic preconditioning. 2 ) sFRP3 was identified as the most significantly upregulated gene in the fourth window and was shown to induce cardioprotection when administered to the hearts of wild-type mice.

The progressive increase in lifespan over the past century carries with it some adversity related to the accompanying burden of debilitating diseases prevalent in the older population. This review focuses on oxidative stress as a major mechanism limiting longevity in general, and healthful aging, in particular. Accordingly, the first goal of this review is to discuss the role of oxidative stress in limiting longevity, and compare healthful aging and its mechanisms in different longevity models. Secondly, we discuss common signaling pathways involved in protection against oxidative stress in aging and in the associated diseases of aging, e.g., neurological, cardiovascular and metabolic diseases, and cancer. Much of the literature has focused on murine models of longevity, which will be discussed first, followed by a comparison with human models of longevity and their relationship to oxidative stress protection. Finally, we discuss the extent to which the different longevity models exhibit the healthful aging features through physiological protective mechanisms related to exercise tolerance and increased β-adrenergic signaling and also protection against diabetes and other metabolic diseases, obesity, cancer, neurological diseases, aging-induced cardiomyopathy, cardiac stress and osteoporosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Protection against increased vascular stiffness in young women is lost after menopause. However, little is known about vascular stiffness in older, premenopausal females, because most of the prior work has been conducted in rodents, which live for only 1-3 yr and do not go through menopause. The goal of the current investigation was to quantitate differences in stiffness down the aortic tree and the mechanisms mediating those differences in older, premenopausal (24 ± 0.7 yr) versus young adult (7 ± 0.7 yr) female nonhuman primates. Aortic stiffness (β), calculated from direct and continuous measurements of aortic diameter and pressure in chronically instrumented, conscious macaque monkeys, increased 2.5-fold in the thoracic aorta and fivefold in the abdominal aorta in old premenopausal monkeys. The aortic histological mechanisms mediating increased vascular stiffness, i.e., collagen/elastin ratio, elastin, and collagen disarray, and the number of breaks in elastin and collagen fibers were greater in the old premenopausal versus young monkeys and greater in the abdominal versus the thoracic aorta and greatest in the iliac artery. In addition, more immature and less cross-linked fibers of collagen were found in the aortas of young females. Aortic stiffness increased in old premenopausal female monkeys, more so in the abdominal aorta than in the thoracic aorta. Histological mechanisms mediating the increased aortic stiffness were augmented in the old premenopausal females, greater in the abdominal versus the thoracic aorta, and greatest in the iliac artery. NEW & NOTEWORTHY This is the first study to examine vascular stiffness down the aortic tree in aging premenopausal females (24 ± 0.7 yr old), whereas prior work studied mainly rodents, which are short-lived and do not undergo menopause. Histological mechanisms mediating vascular stiffness in older premenopausal females increased progressively down the aortic tree, with greater increases in the abdominal aorta compared with the thoracic aorta and with the greatest increases and differences observed in the iliac artery.

Our hypothesis is that Secreted Frizzled-Related Protein 2 (sFPR2) is an important mechanism mediating ischemic cardioprotection, since it is the most upregulated gene in the third window of ischemic preconditioning. One week after permanent coronary artery occlusion (CAO), sFRP2 TG mice exhibited a 49% higher LV ejection fraction and a 36% reduction in infarct size, p < 0.05, and reduced fibrosis in both adjacent and remote zones, along with an increase in collagen type III and a decrease in the collagen type I/III ratio compared with WTL. The ischemic cardioprotection was associated with increased angiogenesis and arteriogenesis, reflected by increased capillary and arteriolar proliferation in the ischemic zone, thereby preserving blood flow after CAO. The angiogenesis and arteriogenesis were mediated by cross talk between myocytes and endothelial cells. The mechanism for cardioprotection and angiogenesis/arteriogenesis did not involve a traditional vascular growth hormone, e.g., VEGF or FGF, but rather cTGF, and ATF6 through the stress signaling pathway. The ATF6 inhibitor, AEBSF, blocked the upregulation of cTGF and both the angiogenesis and arteriogenesis, resulting in abolition of the reduced infarct size and protection of cardiac function in the sFRP2 TG mouse following permanent CAO. sFRP2 is a novel mechanism to induce angiogenesis/arteriogenesis, mediated through the endoplasmatic reticulum (ER) stress signaling pathway, ATF6 and cTGF, which protects the heart from myocardial ischemia.

The mammalian gut microbiome can potentially impact host health and disease state. It is known that the mouse-genome, eating-behavior, and exercise-status promotes higher taxonomic rank-level alterations (e.g. family to phyla-level) of the gut microbiota. Here, host genotype or activity status was investigated to determine if selection of individual bacterial species or strains could be discerned within the murine digestive system. For this study, the fecal bacterial community of adenylyl cyclase 5 knock-out (AC5KO, n = 7) mice or their wild-type (WT, n = 10) littermates under exercise or sedentary conditions were profiled by sequencing rRNA operons. AC5KO mice were chosen since this genotype displays enhanced longevity/exercise capacity and protects against cardiovascular/metabolic disease. Profiling of rRNA operons using the Oxford MinION yielded 65,706 2-D sequences (after size selection of 3.7-5.7 kb) which were screened against an NCBI 16S rRNA gene database. These sequences were binned into 1,566 different best BLAST hits (BBHs) and counted for each mouse sample. Non-metric multidimensional scaling (NMDS) of the gut microbial community demonstrated clustering by physical activity (p = 0.001) but not by host genotype. Additionally, sequence similarity and phylogenetic analysis demonstrated that different bacterial species (closely related to Muribaculum intestinale and Parasutterella excrementihominis) inhabit AC5KO or WT mice depending on activity status. Other bacterial species of the gut microbiota did not follow such patterning (e.g. Turicibacter sanguinis and Turicimonas muris). Our results support the need of improved taxonomic resolution for better characterization of bacterial communities to deepen our understanding of the role of the gut microbiome on host health.

The goal of this investigation was to compare the effects of chronic (4 wk) transverse aortic constriction (TAC) in Sprague-Dawley rats and C57BL/6J mice. TAC, after 1 day, induced similar left ventricular (LV) pressure gradients in both rats ( n = 7) and mice ( n = 7) (113 ± 5.4 vs. 103 ± 11.5 mmHg), and after 4 wk, the percent increase in LV hypertrophy, as reflected by LV/tibial length (51% vs 49%), was similar in rats ( n = 12) and mice ( n = 12). After 4 wk of TAC, LV systolic and diastolic function were preserved in TAC rats. In contrast, in TAC mice, LV ejection fraction decreased by 31% compared with sham, along with increases in LV end-diastolic pressure (153%) and LV systolic wall stress (86%). Angiogenesis, as reflected by Ki67 staining of capillaries, increased more in rats ( n = 6) than in mice ( n = 6; 10 ± 2 vs. 6 ± 1 Ki67-positive cells/field). Myocardial blood flow fell by 55% and coronary reserve by 28% in mice with TAC ( n = 4), but they were preserved in rats ( n = 4). Myogenesis, as reflected by c-kit-positive myocytes staining positively for troponin I, is another mechanism that can confer protection after TAC. However, the c-kit-positive cells in rats with TAC were all negative for troponin I, indicating the absence of myogenesis. Thus, rats showed relative tolerance to severe pressure overload compared with mice, with mechanisms involving angiogenesis but not myogenesis.

Sex differences are an important component of National Institutes of Health rigor. The goal of this investigation was to test the hypothesis that female mice have greater exercise capacity than male mice, and that it is due to estrogen, nitric oxide, and myosin heavy chain expression. Female C57BL6/J wild-type mice exhibited greater ( P < 0.05) maximal exercise capacity for running distance (489 ± 15 m) than age-matched male counterparts (318 ± 15 m), as well as 20% greater work to exhaustion. When matched for weight or muscle mass, females still maintained greater exercise capacity than males. Increased type I and decreased type II myosin heavy chain fibers in the soleus muscle from females are consistent with fatigue resistance and better endurance in females compared with males. After ovariectomy, female mice no longer demonstrated enhanced exercise, and treatment of male mice with estrogen resulted in exercise capacity similar to that of intact females (485 ± 37 m). Nitric oxide synthase, a downstream target of estrogen, exhibited higher activity in female mice compared with male mice, P < 0.05, whereas ovariectomized females exhibited nitric oxide synthase levels similar to males. Nitric oxide synthase activity also increased in males treated with chronic estrogen to levels of intact females. Nitric oxide synthase blockade with N ω -nitro-l-arginine methyl ester eliminated the sex differences in exercise capacity. Thus estrogen, nitric oxide, and myosin heavy chain expression are important mechanisms mediating the enhanced exercise performance in females.

H11 kinase/Hsp22 (Hsp22) is a small heat shock protein, which, when overexpressed cardiac specifically in transgenic (TG) mice, induces stable left ventricular (LV) hypertrophy. Hsp22 also increases oxidative phosphorylation and mitochondrial reactive oxygen species (ROS) production, mechanisms mediating LV hypertrophy, senescence and reduced lifespan. Therefore, we investigated whether ROS production mediates LV hypertrophy, senescence and reduced life span in Hsp22 TG mice. Survival curves revealed that TG mice had a 48% reduction in their mean life span compared to wild type (WT) mice. This was associated with a significant increase in senescence markers, such as p16, p19 mRNA levels as well as the percentage of β-galactosidase positive cells and telomerase activity. Oxidized (GSSG)/reduced (GSH) glutathione ratio, an indicator of oxidative stress, and ROS production from 3 major cellular sources was measured in cardiac tissue. Hearts from TG mice exhibited a decrease in GSH/GSSG ratio together with increased ROS production from all sources. To study the role of ROS, mice were treated with the antioxidant Tempol from weaning to their sacrifice. Chronic Tempol treatment abolished oxidative stress and overproduction of ROS, and reduced myocardial hypertrophy and Akt phosphorylation in TG mice. Tempol also significantly extended life span and prevented aging markers in TG mice. Taken together these results show that overexpression of Hsp22 increases oxidative stress responsible for the induction of hypertrophy and senescence and ultimately reduction in life span., (Copyright © 2019. Published by Elsevier Inc.)

We developed a novel adenylyl cyclase type 5 (AC5) inhibitor, C90, that reduces myocardial infarct size even when administered after coronary reperfusion. This is key, since it is not practical to administer a drug to a patient with myocardial infarction before revascularization, and is one reason why so many prior drugs, which reduced infarct in experimental animals, failed in clinical trials. C90 is the most potent AC5 inhibitor, as exhibited by its IC50 value for AC5 inhibition, which was 5 times lower than the next most potent AC5 inhibitor. C90 reduced cAMP in response to forskolin in wild type mice by 42%, but no longer reduced cAMP in response to forskolin in mice with disruption of AC5, indicating that the mechanism of C90 was specific for AC5 inhibition. Compared with vehicle treatment, C90 reduced infarct size by 64% at a dose of 0.6 mg/kg. Thus, C90 is a novel, selective and potent AC5 inhibitor that reduces infarct size, when delivered after coronary artery reperfusion, rendering it potentially clinically useful. It also reduces beta-adrenergic receptor signaling, which will provide additional benefit to patients with coronary artery disease or heart failure., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hibernating animals show resistance to hypothermia-induced cardiac arrhythmias. However, it is not clear whether and how mammalian hibernators are resistant to ischemia-induced arrhythmias. The goal of this investigation was to determine the susceptibility of woodchucks ( Marmota monax) to arrhythmias and their mechanisms after coronary artery occlusion at the same room temperature in both winter, the time for hibernation, and summer, when they do not hibernate. By monitoring telemetric electrocardiograms, we found significantly higher arrhythmia scores, calculated as the severity of arrhythmias, with incidence of ventricular tachycardia, ventricular fibrillation, and thus sudden cardiac death (SCD) in woodchucks in summer than they had in winter. The level of catalase expression in woodchuck hearts was significantly higher, whereas the level of oxidized Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) was lower in winter than it was in summer. Ventricular myocytes isolated from woodchucks in winter were more resistant to H 2 O 2 -induced early afterdepolarizations (EADs) compared with myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMKII (with KN-93), l-type Ca current (with nifedipine), or late Na + current (with ranolazine). In woodchucks, in the summer, the arrhythmia score was significantly reduced by overexpression of catalase ( via adenoviral vectors) or the inhibition of CaMKII (with KN-93) in the heart. This study suggests that the heart of the mammalian hibernator is more resistant to ischemia-induced arrhythmias and SCD in winter. Increased antioxidative capacity and reduced CaMKII activity may confer resistance in woodchuck hearts against EADs and arrhythmias during winter. The profound protection conferred by catalase overexpression or CaMKII inhibition in this novel natural animal model may provide insights into clinical directions for therapy of arrhythmias.-Zhao, Z., Kudej, R. K., Wen, H., Fefelova, N., Yan, L., Vatner, D. E., Vatner, S. F., Xie, L.-H. Antioxidant defense and protection against cardiac arrhythmias: lessons from a mammalian hibernator (the woodchuck).

Disruption of the regulator for G protein signaling 14 (RGS14) knockout (KO) in mice extends their lifespan and has multiple beneficial effects related to healthful aging, that is, protection from obesity, as reflected by reduced white adipose tissue, protection against cold exposure, and improved metabolism. The observed beneficial effects were mediated by improved mitochondrial function. But most importantly, the main mechanism responsible for the salutary properties of the RGS14 KO involved an increase in brown adipose tissue (BAT), which was confirmed by surgical BAT removal and transplantation to wild-type (WT) mice, a surgical simulation of a molecular knockout. This technique reversed the phenotype of the RGS14 KO and WT, resulting in loss of the improved metabolism and protection against cold exposure in RGS14 KO and conferring this protection to the WT BAT recipients. Another mechanism mediating the salutary features in the RGS14 KO was increased SIRT3. This mechanism was confirmed in the RGS14 X SIRT3 double KO, which no longer demonstrated improved metabolism and protection against cold exposure. Loss of function of the Caenorhabditis elegans RGS-14 homolog confirmed the evolutionary conservation of this mechanism. Thus, disruption of RGS14 is a model of healthful aging, as it not only enhances lifespan, but also protects against obesity and cold exposure and improves metabolism with a key mechanism of increased BAT, which, when removed, eliminates the features of healthful aging., (© 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild-type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise-trained WT to levels already attained in untrained AC5 KO. Exercise training in AC5 KO further enhanced their exercise performance. The key difference in untrained AC5 KO and exercise-trained WT was the β-adrenergic receptor signaling, which was decreased in untrained AC5 KO compared to untrained WT but was increased in WT with exercise training. Despite this key difference, untrained AC5 KO and exercise-trained WT mice shared similar gene expression, determined by deep sequencing, in their gastrocnemius muscle with 183 genes commonly up or down-regulated, mainly involving muscle contraction, metabolism and mitochondrial function. The SIRT1/PGC-1α pathway partially mediated the enhanced exercise in both AC5 KO and exercise-trained WT mice, as reflected in the reduced exercise responses after administering a SIRT1 inhibitor, but did not abolish the enhanced exercise performance in the AC5 KO compared to untrained WT. Increasing oxidative stress with paraquat attenuated exercise performance more in untrained WT than untrained AC5 KO, reflecting the augmented oxidative stress protection in AC5 KO. Blocking nitric oxide actually reduced the enhanced exercise performance in untrained AC5 KO and trained WT to levels below untrained WT, demonstrating the importance of this mechanism. These results suggest that AC5 KO mice, without exercise training, share similar mechanisms responsible for enhanced exercise capacity with chronic exercise training, most importantly increased nitric oxide, and demonstrate more reserve with the addition of exercise training. A novel feature of the enhanced exercise performance in untrained AC5 KO mice is their decreased sympathetic tone, which is also beneficial to patients with cardiovascular disease.

A Food and Drug Administration-approved antiviral agent, known as vidarabine or adenine 9-β-D-arabinofuranoside (AraA), has features of inhibiting adenylyl cyclase type 5 (AC5) and protects against chronic coronary artery occlusion (CAO). The goal of this investigation was to determine whether AraA protects against myocardial ischemia, even when delivered after coronary artery reperfusion (CAR). AraA, delivered after CAR in wild-type mice, reduced infarct size by 55% compared with vehicle-treated controls, whereas an equal dose of adenosine reduced infarct size only when administered before CAR. A 5-fold greater dose of adenosine was required to reduce infarct size when delivered after CAR, which also reduced arterial pressure by 15%, whereas AraA did not affect pressure. The reduction in infarct size with AraA was prevented by a MEK/extracellular signal-regulated kinase blocker, a pathway also involved in the mechanism of protection of the AC5 knockout (KO) model. Infarct size was also reduced in cardiac-specific AC5 KO mice similarly in the presence and absence of AraA, further suggesting that AraA protection involves the AC5 pathway. AraA reduced infarct size in chronically instrumented conscious pigs when delivered after CAR, and in this model, it also reduced post-CAR coronary hyperemia, which could be another mechanism for cardioprotection (i.e., by reducing oxidative stress during CAR). Thus, AraA inhibits AC5 and exhibits unique cardioprotection when delivered after CAR, which is critical for clinical translation., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Since the discovery of a novel mechanism of cell death that differs from traditional necrosis, i.e., apoptosis, there have been numerous studies concluding that increased apoptosis augments myocardial infarction and heart failure and that limiting apoptosis protects the heart. Importantly, the vast majority of cells in the heart are non-myocytes with only roughly 30 % myocytes, yet almost the entire field studying apoptosis in the heart has disregarded non-myocyte apoptosis, e.g., only 4.7 % of 423 studies on myocardial apoptosis in the past 3 years quantified non-myocyte apoptosis. Accordingly, we reviewed the history of apoptosis in the heart focusing first on myocyte apoptosis, followed by the history of non-myocyte apoptosis in myocardial infarction and heart failure. Apoptosis of several of the major non-myocyte cell types in the heart (cardiac fibroblasts, endothelial cells, vascular smooth muscle cells, macrophages and leukocytes) may actually be responsible for affecting the severity of myocardial infarction and heart failure. In summary, even though it is now known that the majority of apoptosis in the heart occurs in non-myocytes, very little work has been done to elucidate the mechanisms by which non-myocyte apoptosis might be responsible for the adverse effects of apoptosis in myocardial infarction and heart failure. The goal of this review is to provide an impetus for future work in this field on non-myocyte apoptosis that will be required for a better understanding of the role of apoptosis in the heart.

Objective: Increased vascular stiffness is central to the pathophysiology of aging, hypertension, diabetes mellitus, and atherosclerosis. However, relatively few studies have examined vascular stiffness in both the thoracic and the abdominal aorta with aging, despite major differences in anatomy, embryological origin, and relation to aortic aneurysm., Approach and Results: The 2 other unique features of this study were (1) to study young (9±1 years) and old (26±1 years) male monkeys and (2) to study direct and continuous measurements of aortic pressure and thoracic and abdominal aortic diameters in conscious monkeys. As expected, aortic stiffness, β, was increased P<0.05, 2- to 3-fold, in old versus young thoracic aorta and augmented further with superimposition of acute hypertension with phenylephrine. Surprisingly, stiffness was not greater in old thoracic aorta than in young abdominal aorta. These results can be explained, in part, by the collagen/elastin ratio, but more importantly, by disarray of collagen and elastin, which correlated best with vascular stiffness. However, vascular smooth muscle cell stiffness was not different in thoracic versus abdominal aorta in either young or old monkeys., Conclusions: Thus, aortic stiffness increases with aging as expected, but the most severe increases in aortic stiffness observed in the abdominal aorta is novel, where values in young monkeys equaled, or even exceeded, values of thoracic aortic stiffness in old monkeys. These results can be explained by alterations in collagen/elastin ratio, but even more importantly by collagen and elastin disarray., (© 2016 American Heart Association, Inc.)

The most important physiological mechanism mediating enhanced exercise performance is increased sympathetic, beta adrenergic receptor (β-AR), and adenylyl cyclase (AC) activity. This is the first report of decreased AC activity mediating increased exercise performance. We demonstrated that AC5 disruption, that is, knock out (KO) mice, a longevity model, increases exercise performance. Importantly for its relation to longevity, exercise was also improved in old AC5 KO. The mechanism resided in skeletal muscle rather than in the heart, as confirmed by cardiac- and skeletal muscle-specific AC5 KO's, where exercise performance was no longer improved by the cardiac-specific AC5 KO, but was by the skeletal muscle-specific AC5 KO, and there was no difference in cardiac output during exercise in AC5 KO vs. WT. Mitochondrial biogenesis was a major mechanism mediating the enhanced exercise. SIRT1, FoxO3a, MEK, and the anti-oxidant, MnSOD were upregulated in AC5 KO mice. The improved exercise in the AC5 KO was blocked with either a SIRT1 inhibitor, MEK inhibitor, or by mating the AC5 KO with MnSOD hetero KO mice, confirming the role of SIRT1, MEK, and oxidative stress mechanisms. The Caenorhabditis elegans worm AC5 ortholog, acy-3 by RNAi, also improved fitness, mitochondrial function, antioxidant defense, and lifespan, attesting to the evolutionary conservation of this pathway. Thus, decreasing sympathetic signaling through loss of AC5 is not only a mechanism to improve exercise performance, but is also a mechanism to improve healthful aging, as exercise also protects against diabetes, obesity, and cardiovascular disease, which all limit healthful aging., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

In recent decades, the pervasiveness of increased arterial stiffness in patients with cardiovascular disease has become increasingly apparent. Though, this phenomenon has been well documented in humans and animal models of disease for well over a century, there has been surprisingly limited development in a deeper mechanistic understanding of arterial stiffness. Much of the historical literature has focused on changes in extracellular matrix proteins-collagen and elastin. However, extracellular matrix changes alone appear insufficient to consistently account for observed changes in vascular stiffness, which we observed in our studies of aortic stiffness in aging monkeys. This led us to examine novel mechanisms operating at the level of the vascular smooth muscle cell (VSMC)-that include increased cell stiffness and adhesion to extracellular matrix-which that may be interrelated with other mechanisms contributing to arterial stiffness. We introduce these observations as a new concept-the Smooth Muscle Cell Stiffness Syndrome (SMCSS)-within the field of arterial stiffness and posit that stiffening of vascular cells impairs vascular function and may contribute stiffening to the vasculature with aging and cardiovascular disease. Importantly, this review article revisits the structural basis of arterial stiffness in light of these novel findings. Such classification of SMCSS and its contextualization into our current understanding of vascular mechanics may be useful in the development of strategic therapeutics to directly target arterial stiffness.