American journal of physiology. Heart and circulatory physiology最新文献

The adipokine chemerin supports normal blood pressure and contributes to adiposity-associated hypertension, evidenced by falls in mean arterial pressure in Dahl SS rats given an antisense oligonucleotide against chemerin. In humans, circulating chemerin is positively associated with hypertension and aortic stiffness. Mechanisms of chemerin's influence on vascular health and disease remain unknown. We identified chemerin production in the vasculature-the blood vessel and its perivascular adipose tissue (PVAT). Here, using RNAScope, qPCR, isometric contractility, high-frequency ultrasound imaging, and Western blot in the Dahl SS rat, we test the hypothesis that endogenous chemerin amplifies agonist-induced vasoconstriction through the chemerin1 receptor and that chemerin drives aortic stiffness in the thoracic aorta. CMKLR1 (chemerin1) expression was higher in the media, and Rarres2 (chemerin) expression was higher in the PVAT. Chemerin1 receptor antagonism via selective inhibitor CCX832 reduced maximal contraction to norepinephrine (NE) and serotonin (5-HT), but not angiotensin II, in isolated thoracic aorta (PVAT intact) from male Dahl SS rat. In females, CCX832 did not alter contraction to NE or 5-HT. Male, but not female, genetic chemerin knockout Dahl SS rats had lower aortic arch pulse wave velocity than wild types, indicating chemerin's role in aortic stiffness. Aortic PVAT from females expressed less chemerin protein than males, suggesting PVAT as the primary source of active chemerin. We show that chemerin made by the PVAT amplifies NE and 5-HT-induced contraction and potentially induces aortic stiffening in a sex-dependent manner, highlighting the potential for chemerin to be a key factor in blood pressure control and aortic stiffening.NEW & NOTEWORTHY Chemerin1 receptor inhibition reduced norepinephrine (NE) and 5-HT-induced vasoconstriction in males. Genetic chemerin knockout (KO) resulted in lower pulse wave velocity in males. Differences in chemerin abundance in aorta perivascular adipose tissue (APVAT) may explain sex-dependent role of chemerin.

The global population of individuals with cardiovascular disease is expanding, and a key risk factor for major adverse cardiovascular events is vascular calcification. The pathogenesis of cardiovascular calcification is complex and multifaceted, with external cues driving epigenetic, transcriptional, and metabolic changes that promote vascular calcification. This review provides an overview of some of the lesser understood molecular processes involved in vascular calcification and discusses the links between calcification pathogenesis and aspects of adenosine signaling and the methionine pathway; the latter of which salvages the essential amino acid methionine, but also provides the substrate critical for methylation, a modification that regulates the function and activity of DNA and proteins. We explore the complex and dynamic nature of osteogenic reprogramming underlying intimal atherosclerotic calcification and medial arterial calcification (MAC). Atherosclerotic calcification is more widely studied; however, emerging studies now show that MAC is a significant pathology independent from atherosclerosis. Furthermore, we emphasize metabolite and metabolic-modulating factors that influence vascular calcification pathogenesis. Although the contributions of these mechanisms are more well-define in relation to atherosclerotic intimal calcification, understanding these pathways may provide crucial mechanistic insights into MAC and inform future therapeutic approaches. Herein, we highlight the significance of adenosine and methyltransferase pathways as key regulators of vascular calcification pathogenesis.

Vascular dysfunction has emerged as a significant risk factor for the development of cardio- and cerebrovascular diseases (CVDs), which are currently the leading cause of morbidity and mortality worldwide. T lymphocytes (T cells) have been shown to be important modulators of vascular function in primary aging and CVDs, likely by producing inflammatory cytokines and reactive oxygen species that influence vasoprotective molecules. This review summarizes the role of T cells on vascular function in aging, hypertension, and atherosclerosis in animals and humans, and discusses potential T-cell targeted therapeutics to prevent, delay, or reverse vascular dysfunction.

About 26 million people worldwide live with heart failure (HF), and hypertension is the primary cause in 25% of these cases. Autonomic dysfunction and sympathetic hyperactivity accompany cardiovascular diseases, including HF. However, changes in cardiac sympathetic innervation in HF are not well understood. We hypothesized that cardiac sympathetic innervation is disrupted in hypertension-induced HF. Male and female C57BL6/J mice were infused with angiotensin II (ANG II) for 4 wk to generate hypertension leading to HF; controls were infused with saline. ANG II-treated mice displayed HF phenotype, including reduced cardiac function, hypertrophy, and fibrosis. ANG II-treated mice also had significantly reduced sympathetic nerve density in the left ventricle, intraventricular septum, and right ventricle. In the left ventricle, the subepicardium remained normally innervated, whereas the subendocardium was almost devoid of sympathetic nerves. Loss of sympathetic fibers led to loss of norepinephrine content in the left ventricle. Several potential triggers for axon degeneration were tested and ruled out. ANG II-treated mice had increased premature ventricular contractions after isoproterenol and caffeine injection. Although HF can induce a cholinergic phenotype and neuronal hypertrophy in stellate ganglia, ANG II treatment did not induce a cholinergic phenotype or activation of trophic factors in this study. Cardiac neurons in the left stellate ganglion were significantly smaller in ANG II-treated mice, whereas neurons in the right stellate were unchanged. Our findings show that ANG II-induced HF disrupts sympathetic innervation, particularly in the left ventricle. Further investigations are imperative to unveil the mechanisms of denervation in HF and to develop neuromodulatory therapies for patients with autonomic imbalance.NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension leads to a heart failure phenotype and cardiac sympathetic denervation with the endocardial region of the left ventricle being the most affected. Denervation is accompanied by loss of norepinephrine content in the left ventricle and increased premature ventricular contractions (PVCs) after isoproterenol and caffeine injection. ANG II treatment also causes morphological changes in cardiac-projecting left stellate ganglion neurons.

Sacubitril/valsartan improves outcomes in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LVEF ≤ 40% were enrolled prospectively. Noninvasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance (E_es; a measure of LV contractility), effective arterial elastance (E_a; a measure of afterload), and the ventricular-arterial coupling ratio (E_a/E_es). The mean age was 65 ± 13 yr, 30% were female, and 54.7% had ischemic heart disease. During 6 mo of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. About 102 patients were included in pressure-volume analyses. After 6 mo of sacubitril/valsartan treatment, E_es increased (0.66 mmHg/mL [IQR 0.45-0.94] vs. 0.78 mmHg/mL [IQR 0.57-1.10], P = 0.001), E_a decreased (1.76 mmHg/mL [IQR 1.48-2.13] vs. 1.62 mmHg/mL [IQR 1.36-1.96], P = 0.014), and the E_a/E_es ratio improved (2.52 [IQR 1.88-4.05] vs. 1.93 [IQR 1.50-2.63], P < 0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both P < 0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-min walking distance. Change in LVEF correlated with change in E_es (r = 0.33, P = 0.0008), while change in NT-proBNP was associated with change in LV end-diastolic pressure (LVEDP) (r = 0.42, P < 0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF.NEW & NOTEWORTHY The study demonstrates that 6-mo treatment with sacubitril/valsartan in patients with heart failure with reduced ejection fraction is associated with increased left ventricular contractility, reduced afterload, and improved ventricular-arterial coupling. Together with reverse remodeling, these changes indicate a leftward shift of the operating left ventricular pressure-volume relationship. These data provide new insights into the understanding of pharmacological mechanisms in the failing heart and may facilitate tailored medical therapy.

The porcine and human heart are remarkably similar in cardiac physiology and biochemistry. Translational research involving the porcine biomedical model is becoming increasingly applicable for the study of human cardiac function in health and disease. Presently, few protocols exist for collecting experimentally viable cardiac tissue from large animal models, particularly during neonatal maturation. To address this deficiency, we have developed a technique to procure and preserve ventricular tissue from neonatal piglets at day 3 (n = 4) and day 30 (n = 6) postpartum. Piglets were subjected to a strict sedation, anesthesia, and analgesia regimen. During surgery, cardiopulmonary indices of electrocardiogram, heart rate, systolic and diastolic blood pressure, respiration rate, peripheral O₂ saturation, and end-tidal CO₂ were monitored continuously to ensure normal cardiac function. Before cardiectomy, each heart was perfused with an intravenous administration of heparin (10 mL/kg) and ice-cold Custodiol HTK cardioplegia solution (10 mL/kg). After cardiac explantation, myocardial samples (dimensions: 1 × 1 × 1 cm) were dissected from the left and right ventricles and snap-frozen in liquid nitrogen. Analysis via SDS-PAGE densitometry demonstrated that myofibrillar proteins are stable and undegraded. Western Blots showed full expression of protein. These results suggest that the detailed cardiac tissue procurement technique preserves the experimental viability of the cardiac tissue and prevents the degradation of myofibrillar proteins.NEW & NOTEWORTHY This project's objective was to develop a technique for procuring and preserving cardiac tissue from a porcine model. Porcine is a rapidly emerging animal model to study cardiovascular disease and has recently been popularized due to advancements in CRISPR-cas9 technology. The technique, originally derived from human heart transplant protocols, involves full anesthetic and analgesic regimens and the use of saline heparin and cardioplegia solution to preserve tissue integrity.

The lack of animal models that accurately represent heart failure with preserved ejection fraction (HFpEF) has been a major barrier to the mechanistic understanding and development of effective therapies for this prevalent and debilitating syndrome characterized by multisystem impairments. Herein, we describe the development and characterization of a novel large animal model of HFpEF in older, female sheep with chronic 2-kidney, 1-clip hypertension. At 6-wk post unilateral renal artery clipping, hypertensive HFpEF sheep had higher mean arterial pressure compared with similarly aged ewes without unilateral renal artery clipping (mean arterial pressure = 112.7 ± 15.9 vs. 76.0 ± 10.1 mmHg, P < 0.0001). The hypertensive HFpEF sheep were characterized by 1) echocardiographic evidence of diastolic dysfunction (lateral e' = 0.11 ± 0.02 vs. 0.14 ± 0.04 m/s, P = 0.011; lateral E/e' = 4.25 ± 0.77 vs. 3.63 ± 0.54, P = 0.028) and concentric left ventricular hypertrophy without overt systolic impairment, 2) elevated directly measured left ventricular end-diastolic pressure (13 ± 5 vs. 0.5 ± 1 mmHg, P = 2.1 × 10^-6), and 3) normal directly measured cardiac output. Crucially, these hypertensive HFpEF sheep had impaired exercise capacity as demonstrated by their 1) attenuated cardiac output (P = 0.001), 2) augmented pulmonary capillary wedge pressure (P = 0.026), and 3) attenuated hindlimb blood flow (P = 3.4 × 10^-4) responses, during graded treadmill exercise testing. In addition, exercise renal blood flow responses were also altered. Collectively, our data indicates that this novel ovine model of HFpEF may be a useful translational research tool because it exhibits similar and clinically relevant impairments as that of patients with HFpEF.NEW & NOTEWORTHY We show that older, female sheep with chronic 2-kidney, 1-clip hypertension have similar cardiac and noncardiac exercise hemodynamic abnormalities as patients with HFpEF. This clinically relevant, translatable, and novel large animal model of HFpEF may be useful for elucidating mechanisms and developing treatments for this increasingly common syndrome with few clinically impactful therapies.

Understanding the cellular mechanisms behind diabetes-related cardiomyopathy is crucial as it is a common and deadly complication of diabetes mellitus. Dysregulation of the mitochondrial genome has been linked to diabetic cardiomyopathy and can be ameliorated by altering microRNA (miRNA) availability in the mitochondrion. Long noncoding RNAs (lncRNAs) have been identified to downregulate miRNAs. This study aimed to determine if diabetes mellitus impacts the mitochondrial localization of lncRNAs, their interaction with miRNAs, and how this influences mitochondrial and cardiac function. In mouse and human nondiabetic and type 2 diabetic cardiac tissue, RNA was isolated from purified mitochondria and sequenced (Ilumina HiSeq). Malat1 was significantly downregulated in both human and mouse cardiac mitochondria. The use of a mouse model with an insertional deletion of Malat1 transcript expression resulted in exacerbated systolic and diastolic dysfunction when evaluated in conjunction with a high-fat diet. The cardiac effects of a high-fat diet were countered in a mouse model with transgenic overexpression of Malat1. MiR-320a, a miRNA that binds to both mitochondrial genome-encoded gene NADH-ubiquinone oxidoreductase chain 1 (MT-ND1) as well as Malat1, was upregulated in human and mouse diabetic mitochondria. Conversely, MT-ND1 was downregulated in human and mouse diabetic mitochondria. Mice with an insertional inactivation of Malat1 displayed increased recruitment of both miR-320a and MT-ND1 to the RNA-induced silencing complex (RISC). In vitro pulldown assays of Malat1 fragments with conserved secondary structure confirmed binding capacity for miR-320a. In vitro Seahorse assays indicated that Malat1 knockdown and miR-320a overexpression impaired overall mitochondrial bioenergetics and Complex I functionality. In summary, the disruption of Malat1 presence in mitochondria, as observed in diabetic cardiomyopathy, is linked to cardiac dysfunction and mitochondrial genome regulation.NEW & NOTEWORTHY Currently, there is no known mechanism for the development of diabetes-related cardiac dysfunction. Previous evaluations have shown that mitochondria, specifically mitochondrial genome-encoded transcripts, are disrupted in diabetic cardiac cells. This study explores the presence of long noncoding RNAs (lncRNAs) such as Malat1 in cardiac mitochondria and how that presence is impacted by diabetes mellitus. Furthermore, this study will examine how the loss of Malat1 results in bioenergetic and cardiac dysfunction through mitochondrial transcriptome dysregulation.