MicroRNAs in Obesity-Associated Disorders: The Role of Exercise Training.

Obesity is a worldwide epidemic affecting over 13% of the adult population and is defined by an excess of body fat that predisposes comorbidities. It is considered a multifactorial disease in which environmental and genetic factors interact, and it is a risk marker for cardiovascular disease. Lifestyle modifications remain the mainstay of treatment for obesity based on adequate diet and physical exercise. In addition, obesity is related to cardiovascular and skeletal muscle disorders, such as cardiac hypertrophy, microvascular rarefaction, and skeletal muscle atrophy. The discovery of obesity-involved molecular pathways is an important step to improve both the prevention and management of this disease. MicroRNAs (miRNAs) are a class of gene regulators which bind most commonly, but not exclusively, to the 3'-untranslated regions of messenger RNAs of protein-coding genes and negatively regulate their expression. Considerable effort has been made to identify miRNAs and target genes that predispose to obesity. Besides their intracellular function, recent studies have demonstrated that miRNAs can be exported or released by cells and circulate within the blood in a remarkably stable form. The discovery of circulating miRNAs opens up intriguing possibilities for the use of circulating miRNA patterns as biomarkers for obesity and cardiovascular diseases. The aim of this review is to provide an overview of the recent discoveries of the role played by miRNAs in the obese phenotype and associated comorbidities. Furthermore, we will discuss the role of exercise training on regulating miRNAs, indicating the mechanisms related to these alterations.

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II-induced microcirculatory changes in a model of primary hypertension.

OBJECTIVE: We investigated the acute effects of SIM on cerebral microvascular rarefaction and dysfunction in SHRs. METHODS: Male WKY and SHRs were divided into 4 groups of 8 animals each: WKY-CTL and SHR-CTL, treated with 0.9% saline; and WKY+SIM and SHR+SIM, treated with SIM (30 mg/kg/d) for 3 days by gavage. Cerebral FCD was assessed by intravital fluorescence videomicroscopy. mCBF before and after administration within the cranial window of angiotensin II (1 µmol L-1 ) was investigated using laser speckle contrast imaging. RESULTS: Cerebral FCD was reduced in SHR-CTL compared to WKY-CTL (P < .05). SIM increased cerebral FCD in SHRs compared to SHR-CTL (P < .05). The mCBF was reduced in SHR-CTL compared to WKY-CTL (P < .05), and SIM increased mCBF compared with SHR-CTL (P < .05). Angiotensin II elicited a reduction of mCBF in SHR-CTL and increased mCBF in WKY-CTL (SHR-CTL -13.53 ± 2% vs WKY-CTL +13.74 ± 4%; P < .001), which was attenuated in SHRs treated with SIM (SHR+SIM -6.7 ± 1% vs SHR-CTL -13.53 ± 2%; P < .01). CONCLUSIONS: The antihypertensive effect of SIM is associated with an improvement in cerebral microvascular perfusion and capillary density that may help to prevent hypertension-induced cerebrovascular damage independent of cholesterol-lowering.

Early Functional and Structural Microvascular Changes in Hypertension Related to Aging.

It is becoming increasingly clear that both microvascular network alterations and subsequent tissue perfusion defects may precede and predict the development of arterial hypertension and other cardiovascular and metabolic diseases, including diabetes and metabolic syndrome. Moreover, the subsequent functional and structural alterations in microvascular reactivity and density, as well as alterations in the macrocirculation characteristic of physiologic vascular aging, contribute to the development of target organ damage. Microvascular rarefaction appears to be an early vascular structural alteration in the setting of hypertension, as it is already present in individuals presenting with borderline hypertension and normotensive young adults with a familial predisposition to high blood pressure. The chronic increases in blood pressure that occur during senescence secondary to macrocirculatory changes induce vasoconstriction within the microcirculation, which promotes the development of tissue hypoxia and reduces both arteriolar and capillary density. This phenomenon contributes to additional increases in peripheral vascular resistance and establishes a vicious cycle that culminates in both tissue injury and target organ damage, which are equally present in senescence and hypertension. Therefore, the microcirculation may be considered an essential target for both the pharmacological and non-pharmacological treatment of arterial hypertension and other cardiovascular diseases.

Central Sympathetic Modulation Reverses Microvascular Alterations in a Rat Model of High-Fat Diet-Induced Metabolic Syndrome.

OBJECTIVES: The objective of this study was to investigate the role of the SNS on hemodynamic, metabolic, and microvascular alterations in a rat model of HFD-induced MS with salt supplementation. METHODS: In total, 40 adult male Wistar rats were fed normal chow (n = 10) or a HFD (n = 30) for 20 weeks. Thereafter, the HFD group received the centrally acting sympatho-modulatory drugs clonidine (0.1 mg/kg) or rilmenidine (1 mg/kg) or vehicle (n = 10/group) orally by gavage. FCD was evaluated using intravital video microscopy, and the SCD was evaluated using histochemical analysis. RESULTS: The pharmacological modulation of the SNS induced concomitant reductions in SBP, HR and plasma catecholamine levels. These effects were accompanied by a reversal of functional and structural capillary rarefaction in the skeletal muscle in both treated groups and an increase in SCD in the left ventricle only in the rilmenidine group. Improvement of the lipid profile and of glucose intolerance was also obtained only with rilmenidine treatment. CONCLUSIONS: Modulation of sympathetic overactivity results in the reversal of microvascular rarefaction in the skeletal muscle and left ventricle and improves metabolic parameters in an experimental model of MS in rats.

Cardiac microvascular rarefaction in hyperthyroid rats is reversed by losartan, diltiazem, and propranolol.

Cardiac microvascular rarefaction appears to be involved in hyperthyroidism-induced left ventricular hypertrophy and dysfunction. We investigated the effects of losartan, an AT1 receptor antagonist; diltiazem, a calcium channel blocker; and propranolol, a ß-adrenergic receptor antagonist, on cardiac function and structural microcirculatory cardiac alterations in an experimental model of l-thyroxin-induced hyperthyroidism in rats. Hyperthyroidism (HYPER) was induced by intraperitoneal injections of l-thyroxin for 35 days (600 µg/kg/day; n = 32). The euthyroid group was treated with distilled water (EUT + VEH; n = 8). On the 14th day, the HYPER group was divided into four groups that received an oral treatment for 21 days with saline (HYPER + VEH; n = 8), losartan (10 mg/kg/day; HYPER + LOS, n = 8), diltiazem (10 mg/kg/day; HYPER + DILT, n = 8), or propranolol (10 mg/kg/day; HYPER + PROP, n = 8). An echocardiographic study was performed at baseline, at the beginning and at the end of the pharmacological treatment protocol (35th day). The structural capillary density in the left ventricle (LV) was analyzed using histochemical analysis with fluorescein isothiocyanate-conjugated Griffonia simplicifolia lectin. HYPER + VEH (182 ± 5 mmHg; P < 0.001) presented higher systolic blood pressure (SBP) compared with EUT + VEH (132 ± 3 mmHg). HYPER + LOS (144 ± 2 mmHg), HYPER + DILT (147 ± 3 mmHg) and HYPER + PROP (153 ± 4 mmHg) presented lower SBP compared with HYPER + VEH (P < 0.001). Chronic treatment with losartan, diltiazem, and propranolol reversed cardiac structural microvascular rarefaction (HYPER + VEH 0.16 ± 0.01; EUT + VEH 0.35 ± 0.02; HYPER + LOS 0.46 ± 0.03; HYPER + DILT 0.49 ± 0.02; HYPER + PROP 0.58 ± 0.04 (Vv[cap]/Vv[fib]); P < 0.001) and enhanced the LV ejection fraction of hyperthyroid rats (HYPER + VEH 71 ± 3; EUT + VEH 85 ± 2; HYPER + LOS 90 ± 3; HYPER + DILT 85 ± 3; HYPER + PROP 86 ± 2%; P < 0.05). In conclusion, chronic treatment with losartan, diltiazem, and propranolol improved the cardiac microcirculation and function in an experimental model of hyperthyroidism in rats.