Key Enzymes for the Mevalonate Pathway in the Cardiovascular System.

ABSTRACT: Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.

Impaired Cardiovascular Function in Male Rats with Hypo- and Hyperthyroidism: Involvement of Imbalanced Nitric Oxide Synthase Levels.

BACKGROUND AND OBJECTIVE: All three isoforms of nitric oxide (NO) synthase (NOS) are targets for thyroid hormones in the cardiovascular system. The aim of this study was to assess the effects of hypo- and hyperthyroidism on inducible (iNOS), endothelial (eNOS), and neural (nNOS) NOS levels in aorta and heart tissues of male rats. METHODS: Rats were divided into control, hypothyroid, and hyperthyroid groups; hypo- and hyperthyroidism were induced by adding propylthiouracil (500 mg/L) and L-thyroxine (12 mg/L) to drinking water for a period of 21 days. On day 21, systolic blood pressure, heart rate, left ventricular developed pressure (LVDP), peak rate of positive and negative (±dp/dt) changes in left ventricular pressure as well as NO metabolites (NOx) and iNOS, eNOS, and nNOS protein levels in aorta and heart, were all measured. RESULTS: Compared to controls, LVDP and ±dp/dt were lower in both hypo- and hyperthyroid rats. Compared to controls, heart rate and systolic blood pressure were lower in hypothyroid and higher in hyperthyroid rats. NOx levels in the heart of hypothyroid rats were lower (53%), whereas that in hyperthyroid rats were higher (56% and 40%) than controls. Compared to controls, hypothyroid rats had lower levels of eNOS, iNOS, and nNOS in the aorta (16%, 34%, and 15%, respectively) and lower iNOS and higher nNOS in heart tissue (27% and 46%). In hyperthyroid rats, eNOS levels were lower (54% and 30%) and iNOS were higher (63%, and 35%) in the aorta and heart while nNOS was lower in the aorta (18%). CONCLUSION: Hypothyroidism increased while hyperthyroidism decreased the ratio of eNOS/iNOS in aorta and heart; these changes of NOS levels were associated with impaired cardiovascular function.

Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease.

Peptidylarginine deiminase (PAD) family members have a vital role in maintaining the stability of the extracellular matrix (ECM) during remodelling in several heart diseases. PAD-mediated deamination, or citrullination, has been studied in different physiological and pathological conditions in the body. However, the role of PAD isoforms has not been fully studied in cardiovascular system. Citrullination is a post-translational modification that involves conversion of peptidyl-based arginine to peptidyl-based citrulline by PAD family members in a calcium-dependent manner. Upregulation of PADs have been observed in various cardiovascular diseases, including venous thrombosis, cardiac fibrosis, heart failure, atherosclerosis, coronary heart disease and acute inflammation. In this review, experimental aspects of in vivo and in vitro studies related to the roles PAD isoforms in cardiovascular diseases including mechanisms, pathophysiological and therapeutic properties are discussed. Pharmacological strategies for targeting PAD family proteins in cardiac diseases have not yet been studied. Furthermore, the role played by PAD family members in the remodelling process during the progression of cardiovascular diseases is not fully understood.

ACE2, a multifunctional protein - from cardiovascular regulation to COVID-19.

This Editorial, written by Guest Editors Professor Michael Bader, Professor Anthony J. Turner and Dr Natalia Alenina, proudly introduces the Clinical Science-themed collection on angiotensin-converting enzyme 2 (ACE2), a multifunctional protein - from cardiovascular regulation to coronavirus disease 2019 (COVID-19).

Angiotensin II-Induced Cardiovascular Fibrosis Is Attenuated by NO-Sensitive Guanylyl Cyclase1.

In the NO/cGMP signaling cascade, relevant in the cardiovascular system, two NO-sensitive guanylyl cyclase (NO-GC) isoforms are responsible for NO-dependent cGMP generation. Here, the impact of the major NO-GC isoform, NO-GC1, on fibrosis development in the cardiovascular system was studied in NO-GC1-deficient mice treated with AngiotensinII (AngII), known to induce vascular and cardiac remodeling. Morphometric analysis of NO-GC1 KO's aortae demonstrated an enhanced increase of perivascular area after AngII treatment accompanied by a higher aortic collagen1 mRNA content. Increased perivascular fibrosis also occurred in cardiac vessels of AngII-treated NO-GC1 KO mice. In line, AngII-induced interstitial fibrosis was 32% more pronounced in NO-GC1 KO than in WT myocardia associated with a higher cardiac Col1 and other fibrotic marker protein content. In sum, increased perivascular and cardiac interstitial fibrosis together with the enhanced collagen1 mRNA content in AngII-treated NO-GC1-deficient mice represent an exciting manifestation of antifibrotic properties of cGMP formed by NO-GC1, a finding with great pharmaco-therapeutic implications.

Role of neuronal nitric oxide synthase on cardiovascular functions in physiological and pathophysiological states.

This review describes and summarizes the role of neuronal nitric oxide synthase (nNOS) on the central nervous system, particularly on brain regions such as the ventrolateral medulla (VLM) and the periaqueductal gray matter (PAG), and on blood vessels and the heart that are involved in the regulation and control of the cardiovascular system (CVS). Furthermore, we shall also review the functional aspects of nNOS during several physiological, pathophysiological, and clinical conditions such as exercise, pain, cerebral vascular accidents or stroke and hypertension. For example, during stroke, a cascade of molecular, neurochemical, and cellular changes occur that affect the nervous system as elicited by generation of free radicals and nitric oxide (NO) from vulnerable neurons, peroxide formation, superoxides, apoptosis, and the differential activation of three isoforms of nitric oxide synthases (NOSs), and can exert profound effects on the CVS. Neuronal NOS is one of the three isoforms of NOSs, the others being endothelial (eNOS) and inducible (iNOS) enzymes. Neuronal NOS is a critical homeostatic component of the CVS and plays an important role in regulation of different systems and disease process including nociception. The functional and physiological roles of NO and nNOS are described at the beginning of this review. We also elaborate the structure, gene, domain, and regulation of the nNOS protein. Both inhibitory and excitatory role of nNOS on the sympathetic autonomic nervous system (SANS) and parasympathetic autonomic nervous system (PANS) as mediated via different neurotransmitters/signal transduction processes will be explored, particularly its effects on the CVS. Because the VLM plays a crucial function in cardiovascular homeostatic mechanisms, the neuroanatomy and cardiovascular regulation of the VLM will be discussed in conjunction with the actions of nNOS. Thereafter, we shall discuss the up-to-date developments that are related to the interaction between nNOS and cardiovascular diseases such as hypertension and stroke. Finally, we shall focus on the role of nNOS, particularly within the PAG in cardiovascular regulation and neurotransmission during different types of pain stimulus. Overall, this review focuses on our current understanding of the nNOS protein, and provides further insights on how nNOS modulates, regulates, and controls cardiovascular function during both physiological activity such as exercise, and pathophysiological conditions such as stroke and hypertension.

Sestrin2 as a potential therapeutic target for cardiovascular diseases.

Sestrin2 is a cysteine sulfinyl reductase that plays crucial roles in regulation of antioxidant actions. Sestrin2 provides cytoprotection against multiple stress conditions, including hypoxia, endoplasmic reticulum (ER) stress and oxidative stress. Recent research reveals that upregulation of Sestrin2 is induced by various transcription factors such as p53 and activator protein 1 (AP-1), which further promotes AMP-activated protein kinase (AMPK) activation and inhibits mammalian target of rapamycin protein kinase (mTOR) signaling. Sestrin2 triggers autophagy activity to reduce cellular reactive oxygen species (ROS) levels by promoting nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) activation and Kelch-like ECH-associated protein 1 (Keap1) degradation, which plays a pivotal role in homeostasis of metabolic regulation. Under hypoxia and ER stress conditions, elevated Sestrin2 expression maintains cellular homeostasis through regulation of antioxidant genes. Sestrin2 is responsible for diminishing cellular ROS accumulation through autophagy via AMPK activation, which displays cardioprotection effect in cardiovascular diseases. In this review, we summarize the recent understanding of molecular structure, biological roles and biochemical functions of Sestrin2, and discuss the roles and mechanisms of Sestrin2 in autophagy, hypoxia and ER stress. Understanding the precise functions and exact mechanism of Sestrin2 in cellular homeostasis will provide the evidence for future experimental research and aid in the development of novel therapeutic strategies for cardiovascular diseases.

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues.

BACKGROUND: Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 180 000 people worldwide and has caused more than 150 000 deaths as of April 16, 2020. SARS-CoV-2, which is the virus causing coronavirus disease 2019 (COVID-19), uses the angiotensin-converting enzyme 2 (ACE2) as a cell receptor to invade human cells. Thus, ACE2 is the key to understanding the mechanism of SARS-CoV-2 infection. This study is to investigate the ACE2 expression in various human tissues in order to provide insights into the mechanism of SARS-CoV-2 infection. METHODS: We compared ACE2 expression levels across 31 normal human tissues between males and females and between younger (ages ≤ 49 years) and older (ages > 49 years) persons using two-sided Student's t test. We also investigated the correlations between ACE2 expression and immune signatures in various tissues using Pearson's correlation test. RESULTS: ACE2 expression levels were the highest in the small intestine, testis, kidneys, heart, thyroid, and adipose tissue, and were the lowest in the blood, spleen, bone marrow, brain, blood vessels, and muscle. ACE2 showed medium expression levels in the lungs, colon, liver, bladder, and adrenal gland. ACE2 was not differentially expressed between males and females or between younger and older persons in any tissue. In the skin, digestive system, brain, and blood vessels, ACE2 expression levels were positively associated with immune signatures in both males and females. In the thyroid and lungs, ACE2 expression levels were positively and negatively associated with immune signatures in males and females, respectively, and in the lungs they had a positive and a negative correlation in the older and younger groups, respectively. CONCLUSIONS: Our data indicate that SARS-CoV-2 may infect other tissues aside from the lungs and infect persons with different sexes, ages, and races equally. The different host immune responses to SARS-CoV-2 infection may partially explain why males and females, young and old persons infected with this virus have markedly distinct disease severity. This study provides new insights into the role of ACE2 in the SARS-CoV-2 pandemic.

ADAMTS-5: A difficult teenager turning 20.

A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major proteoglycan in articular cartilage. Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA), a disease characterized by extensive degradation of aggrecan. For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. However, ADAMTS-5 proteoglycanase activity is not only involved in the dysregulated aggrecan proteolysis, which occurs in OA, but also in the physiological turnover of other related proteoglycans. In particular, versican, a major ADAMTS-5 substrate, plays an important structural role in heart and blood vessels and its proteolytic processing by ADAMTS-5 must be tightly regulated. On the occasion of the 20th anniversary of the discovery of ADAMTS-5, this review looks at the evidence for its detrimental role in OA, as well as its physiological turnover of cardiovascular proteoglycans. Moreover, the other potential functions of this enzyme are highlighted. Finally, challenges and emerging trends in ADAMTS-5 research are discussed.

Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase.

RATIONALE: Hydrogen sulfide (H2S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H2S, namely cystathionine γ-lyase (CSE), cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present study we determined the importance of 3-MST in the heart and blood vessels, using a genetic model with a global 3-MST deletion. RESULTS: 3-MST is the most abundant transcript in the mouse heart, compared to CSE and CBS. 3-MST was mainly localized in smooth muscle cells and cardiomyocytes, where it was present in both the mitochondria and the cytosol. Levels of serum and cardiac H2S species were not altered in adult young (2-3 months old) 3-MST-/- mice compared to WT animals. No significant changes in the expression of CSE and CBS were observed. Additionally, 3-MST-/- mice had normal left ventricular structure and function, blood pressure and vascular reactivity. Interestingly, genetic ablation of 3-MST protected mice against myocardial ischemia reperfusion injury, and abolished the protection offered by ischemic pre- and post-conditioning. 3-MST-/- mice showed lower expression levels of thiosulfate sulfurtransferase, lower levels of cellular antioxidants and elevated basal levels of cardiac reactive oxygen species. In parallel, 3-MST-/- mice showed no significant alterations in endothelial NO synthase or downstream targets. Finally, in a separate cohort of older 3-MST-/- mice (18 months old), a hypertensive phenotype associated with cardiac hypertrophy and NO insufficiency was observed. CONCLUSIONS: Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with aging it predisposes them to hypertension and cardiac hypertrophy.

Mechanisms of Cardiovascular Toxicity of BCR-ABL1 Tyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia.

PURPOSE OF REVIEW: Oral tyrosine kinase inhibitors have revolutionized the treatment of chronic myelogenous leukemia, with many patients achieving major clinical and molecular responses without complications. While typically well-tolerated, clinical experience with tyrosine kinase inhibitors (particularly those of the second and third generations) has highlighted unanticipated associations with serious non-cancer adverse effects on various organs, particularly the cardiovascular system. RECENT FINDINGS: Herein, we review the current literature surrounding the major cardiovascular toxicities of BCR-ABL1 tyrosine kinase inhibitors in chronic myelogenous leukemia, discuss potential mechanisms underpinning their development, and suggest future research directions to uncover novel ways to reduce cardiovascular events in patients treated with tyrosine kinase inhibitors. As a whole, while cardiovascular toxicities are well-documented, the mechanistic basis of these clinical observations remains poorly defined. In turn, to provide safe and effective treatment to all patients, it is necessary to close the knowledge gap regarding mechanisms that drive toxicity and elucidate the complex interactions that predispose specific individuals to these toxicities.

Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease.

Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.

[Study of energy metabolism enzymes and state of cardiovascular system in elderly and senile age patients.]

The present work introduces data on studying the activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) and the state of the cardiovascular system in elderly and senile people who applied to polyclinic "Health zone" in Baku. 60 people on an enzimopatiya and 87 people on a condition of cardiovascular system were examined. The examined persons were found the decreased myocardial blood flow, ischemic heart disease (IHD), against increased PK and LDH. Statistically significant differences in the activity of enzymes depending on gender, age were established, and changes in the bioelectric activity of the heart during an ECG were detected.

NADPH oxidase in the vasculature: Expression, regulation and signalling pathways; role in normal cardiovascular physiology and its dysregulation in hypertension.

The last 20-25 years have seen an explosion of interest in the role of NADPH oxidase (NOX) in cardiovascular function and disease. In vascular smooth muscle and endothelium, NOX generates reactive oxygen species (ROS) that act as second messengers, contributing to the control of normal vascular function. NOX activity is altered in response to a variety of stimuli, including G-protein coupled receptor agonists, growth-factors, perfusion pressure, flow and hypoxia. NOX-derived ROS are involved in smooth muscle constriction, endothelium-dependent relaxation and smooth muscle growth, proliferation and migration, thus contributing to the fine-tuning of blood flow, arterial wall thickness and vascular resistance. Through reversible oxidative modification of target proteins, ROS regulate the activity of protein tyrosine phosphatases, kinases, G proteins, ion channels, cytoskeletal proteins and transcription factors. There is now considerable, but somewhat contradictory evidence that NOX contributes to the pathogenesis of hypertension through oxidative stress. Specific NOX isoforms have been implicated in endothelial dysfunction, hyper-contractility and vascular remodelling in various animal models of hypertension, pulmonary hypertension and pulmonary arterial hypertension, but also have potential protective effects, particularly NOX4. This review explores the multiplicity of NOX function in the healthy vasculature and the evidence for and against targeting NOX for antihypertensive therapy.

Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges.

Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets.

TAM receptors in cardiovascular disease.

The TAM receptors are a distinct family of three receptor tyrosine kinases, namely Tyro3, Axl, and MerTK. Since their discovery in the early 1990s, they have been studied for their ability to influence numerous diseases, including cancer, chronic inflammatory and autoimmune disorders, and cardiovascular diseases. The TAM receptors demonstrate an ability to influence multiple aspects of cardiovascular pathology via their diverse effects on cells of both the vasculature and the immune system. In this review, we will explore the various functions of the TAM receptors and how they influence cardiovascular disease through regulation of vascular remodelling, efferocytosis and inflammation. Based on this information, we will suggest areas in which further research is required and identify potential targets for therapeutic intervention.

Subclinical coronary atherosclerosis and cardiovascular risk stratification in heterozygous familial hypercholesterolemia patients undergoing statin treatment.

PURPOSE OF REVIEW: To discuss the heterogeneity of atherosclerotic cardiovascular disease (ASCVD) risk in heterozygous familial hypercholesterolemia and evidence and limitations of clinical risk scores and subclinical coronary atherosclerosis (SCA) imaging to evaluate risk. RECENT FINDINGS: Risk evaluation in contemporary familial hypercholesterolemia cohorts needs to consider the cause of the familial hypercholesterolemia phenotype, for example the presence of autosomal molecular defects that impart a greater ASCVD risk than in polygenic hypercholesterolemia, prospective follow-up and the impact of statin treatment. As atherosclerosis is multifactorial, clinical scores like the Montreal familial hypercholesterolemia score and SAFEHEART risk equation have been proposed to stratify ASCVD in statin-treated, molecularly defined familial hypercholesterolemia individuals. However, these scores need further validation. SCA distribution in familial hypercholesterolemia individuals undergoing conventional lipid-lowering treatment is heterogeneous, with 45-50% of individuals not presenting any coronary artery calcification (CAC). One study suggests that the absence of CAC associates with no ASCVD events in asymptomatic familial hypercholesterolemia individuals undergoing statin therapy despite elevated residual LDL-cholesterol levels. In contrast, the presence of CAC was independently associated with ASCVD events. SUMMARY: ASCVD risk is heterogeneous in statin-treated familial hypercholesterolemia individuals. Further studies are necessary to determine how risk stratification, especially with SCA detection, impacts on prescription of proprotein convertase subtilisin kexin type 9 inhibitors within a cost-constrained environment.

Chemiluminescence immunoassay for sensing lipoprotein-associated phospholipase A2 in cardiovascular risk evaluation.

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a novel inflammatory biomarker, which is useful as an adjunct identification tool for cardiovascular disease. However, the important limitation of the conventional enzyme-linked immunosorbent assay (PLAC ELISA) for Lp-PLA2 assay is its relatively low sensitivity and time consuming. A method to measure the Lp-PLA2 simply, rapidly and sensitively is essential for predicting cardiovascular events in clinic. METHODS: We took advantage of magnetic separation integrated with chemiluminescence to detect Lp-PLA2. The concentration of Lp-PLA2 was measured through a one-step process by mixing antibody labelled magnetic beads, antigen and antibody at one time. RESULTS: Our method realized the sample to answer within 17 min. The detection limit and measurement range were 0.18 ng/ml and 0.18-1350 ng/ml, respectively. The specificity assay showed that no appreciable interference was observed for the substances of bilirubin, triglyceride, hemoglobin, rheumatoid factor and human anti-mouse antibody up to the concentrations of 40 mg/dl, 1000 mg/dl, 2000 mg/dl, 1500 IU/ml and 30 ng/ml, separately. We also tested 122 clinical samples using our method, presenting good overall correlations (R2 = 0.979) to the PLAC ELISA. It is worth mentioning that, our method was faster, had a wider range of measurement and higher sensitivity compared with the PLAC ELISA. CONCLUSIONS: The Lp-PLA2 assay is straightforward, sensitive and precise, which is highly suitable to further explore the clinical performance of Lp-PLA2 in studies of cardiovascular risk management.

Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases.

The sirtuin family of nicotinamide adenine dinucleotide-dependent deacylases (SIRT1-7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.

MMP-2: is too low as bad as too high in the cardiovascular system?

Matrix metalloproteinase (MMP)-2 cleaves a broad spectrum of substrates, including extracellular matrix components (responsible for normal tissue remodeling) and cytokines (modulators of the inflammatory response to physiological insults such as tissue damage). MMP-2 expression is elevated in many cardiovascular pathologies (e.g., myocardial infarction, hypertensive heart disease) where tissue remodeling and inflammatory responses are perturbed. Thus, it has generally been assumed that blockade of MMP-2 activity will yield therapeutic effects. Here, we provide a counterargument to this dogma based on 1) preclinical studies on Mmp2-null ( Mmp2-/-) mice and 2) clinical studies on patients with inactivating MMP2 gene mutations. Furthermore, we put forward the hypothesis that, when MMP-2 activity falls below baseline, the bioavailability of proinflammatory cytokines normally cleaved and inactivated by MMP-2 increases, leading to the production of cytokines and cardiac secretion of phospholipase A2 activity into the circulation, which stimulate systemic inflammation that perturbs lipid metabolism in target organs. Finally, we suggest that insufficient understanding of the consequences of MMP-2 deficiency remains a major factor in the failure of MMP-2 inhibitor-based therapeutic approaches. This paucity of knowledge precludes our ability to effectively intervene in cardiovascular and noncardiovascular pathologies at the level of MMP-2.