Adenosine kinase inhibition enhances microvascular dilator function and improves left ventricle diastolic dysfunction.

OBJECTIVE: Inhibition of adenosine kinase (ADK), via augmenting endogenous adenosine levels exerts cardiovascular protection. We tested the hypothesis that ADK inhibition improves microvascular dilator and left ventricle (LV) contractile function under metabolic or hemodynamic stress. METHODS AND RESULTS: In Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid rats, treatment with the selective ADK inhibitor, ABT-702 (1.5 mg/kg, intraperitoneal injections for 8-week) restored acetylcholine-, sodium nitroprusside-, and adenosine-induced dilations in isolated coronary arterioles, an effect that was accompanied by normalized end-diastolic pressure (in mm Hg, Lean: 3.4 ± 0.6, Obese: 17.6 ± 4.2, Obese + ABT: 6.6 ± 1.4) and LV relaxation constant, Tau (in ms, Lean: 6.9 ± 1.5, Obese: 13.9 ± 1.7, Obese + ABT: 6.0 ± 1.1). Mice with vascular endothelium selective ADK deletion (ADKVEC KO) exhibited an enhanced dilation to acetylcholine in isolated gracilis muscle (lgEC50 WT: -8.2 ± 0.1, ADKVEC KO: -8.8 ± 0.1, P < .05) and mesenteric arterioles (lgEC50 WT: -7.4 ± 0.2, ADKVEC KO: -8.1 ± 1.2, P < .05) when compared to wild-type (WT) mice, whereas relaxation of the femoral artery and aorta (lgEC50 WT: -7.03 ± 0.6, ADKVEC KO: -7.05 ± 0.8) was similar in the two groups. Wild-type mice progressively developed LV systolic and diastolic dysfunction when they underwent transverse aortic constriction surgery, whereas ADKVEC -KO mice displayed a lesser degree in decline of LV function. CONCLUSIONS: Our results indicate that ADK inhibition selectively enhances microvascular vasodilator function, whereby it improves LV perfusion and LV contractile function under metabolic and hemodynamic stress.

Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction.

OBJECTIVE: A disintegrin and metalloproteinase ADAM17 (tumor necrosis factor-α [TNF]-converting enzyme) regulates soluble TNF levels. We tested the hypothesis that aging-induced activation in adipose tissue (AT)-expressed ADAM17 contributes to the development of remote coronary microvascular dysfunction in obesity. APPROACH AND RESULTS: Coronary arterioles (CAs, ≈90 µm) from right atrial appendages and mediastinal AT were examined in patients (aged: 69±11 years, BMI: 30.2±5.6 kg/m2) who underwent open heart surgery. CA and AT were also studied in 6-month and 24-month lean and obese mice fed a normal or high-fat diet. We found that obesity elicited impaired endothelium-dependent CA dilations only in older patients and in aged high-fat diet mice. Transplantation of AT from aged obese, but not from young or aged, mice increased serum cytokine levels, including TNF, and impaired CA dilation in the young recipient mice. In patients and mice, obesity was accompanied by age-related activation of ADAM17, which was attributed to vascular endothelium-expressed ADAM17. Excess, ADAM17-shed TNF from AT arteries in older obese patients was sufficient to impair CA dilation in a bioassay in which the AT artery was serially connected to a CA. Moreover, we found that the increased activity of endothelial ADAM17 is mediated by a diminished inhibitory interaction with caveolin-1, owing to age-related decline in caveolin-1 expression in obese patients and mice or to genetic deletion of caveolin-1. CONCLUSIONS: The present study indicates that aging and obesity cooperatively reduce caveolin-1 expression and increase vascular endothelial ADAM17 activity and soluble TNF release in AT, which may contribute to the development of remote coronary microvascular dysfunction in older obese patients.

Long Non-Coding RNAs as Master Regulators in Cardiovascular Diseases.

Cardiovascular disease is the leading cause of death in the United States, accounting for nearly one in every seven deaths. Over the last decade, various targeted therapeutics have been introduced, but there has been no corresponding improvement in patient survival. Since the mortality rate of cardiovascular disease has not been significantly decreased, efforts have been made to understand the link between heart disease and novel therapeutic targets such as non-coding RNAs. Among multiple non-coding RNAs, long non-coding RNA (lncRNA) has emerged as a novel therapeutic in cardiovascular medicine. LncRNAs are endogenous RNAs that contain over 200 nucleotides and regulate gene expression. Recent studies suggest critical roles of lncRNAs in modulating the initiation and progression of cardiovascular diseases. For example, aberrant lncRNA expression has been associated with the pathogenesis of ischemic heart failure. In this article, we present a synopsis of recent discoveries that link the roles and molecular interactions of lncRNAs to cardiovascular diseases. Moreover, we describe the prevalence of circulating lncRNAs and assess their potential utilities as biomarkers for diagnosis and prognosis of heart disease.

Coronary Microvascular Dysfunction and Heart Failure with Preserved Ejection Fraction - implications for Chronic Inflammatory Mechanisms.

Coronary Microvascular Dysfunction (CMD) is now considered one of the key underlying pathologies responsible for the development of both acute and chronic cardiac complications. It has been long recognized that CMD contributes to coronary no-reflow, which occurs as an acute complication during percutaneous coronary interventions. More recently, CMD was proposed to play a mechanistic role in the development of left ventricle diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF). Emerging evidence indicates that a chronic low-grade pro-inflammatory activation predisposes patients to both acute and chronic cardiovascular complications raising the possibility that pro-inflammatory mediators serve as a mechanistic link in HFpEF. Few recent studies have evaluated the role of the hyaluronan-CD44 axis in inflammation-related cardiovascular pathologies, thus warranting further investigations. This review article summarizes current evidence for the role of CMD in the development of HFpEF, focusing on molecular mediators of chronic proinflammatory as well as oxidative stress mechanisms and possible therapeutic approaches to consider for treatment and prevention.

Adenosine Kinase Inhibition Augments Conducted Vasodilation and Prevents Left Ventricle Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is often manifested as impaired cardiovascular reserve. We sought to determine if conducted vasodilation, which coordinates microvascular resistance longitudinally to match tissue metabolic demand, becomes compromised in HFpEF. We hypothesized that the metabolic vasodilator adenosine facilitates and that inhibition of ADK (adenosine kinase) augments conducted vasodilation for a more efficient myocardial perfusion and improved left ventricle (LV) diastolic function in HFpEF. METHODS AND RESULTS: We assessed conducted vasodilation in obese ZSF1 rats that develop LV diastolic dysfunction and is used to model human HFpEF. Additionally, conducted vasodilation was measured in arterioles isolated from the right atrial appendages of patients with HFpEF. We found a markedly reduced conducted vasodilation both in obese ZSF1 rats and in patients with HFpEF. Impaired conducted vasodilation was accompanied by increased vascular ADK expression. Isolated rat and human arterioles incubated with adenosine (10 nmol/L) or ADK inhibitor ABT-702 (0.1 µmol/L) both displayed augmented conducted vasodilation. Treatment of obese ZSF1 rats with ABT-702 (1.5 mg/kg, IP for 8 weeks) prevented LV diastolic dysfunction, and in a crossover design augmented conducted vasodilation and improved LV diastolic function. ABT-702 treated obese ZSF1 rats exhibited reduced expression of myocardial carbonic anhydrase 9 and collagen, surrogate markers of myocardial hypoxia. CONCLUSIONS: Upregulation of vascular ADK mitigates adenosine-facilitated conducted vasodilation in obese ZSF1 rats and in patients with HFpEF. We propose that pharmacological inhibition of ADK could be beneficial for therapeutic augmentation of conducted vasodilation, thereby improving tissue perfusion and LV diastolic function in HFpEF.