Shereen M. Hamza

Obesity-induced Hypertension: Role of Sympathetic Nervous System, Leptin, and Melanocortins

Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors.

Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis

Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.

Role of spleen in integrated control of splanchnic vascular tone : physiology and pathophysiology

Aside from its established immunologic and hematologic functions, the spleen also plays an important role in cardiovascular regulation. This occurs through changes in intrasplenic microvascular tone, as well as through splenic neurohormonal modulation of the renal and mesenteric vascular beds. Splenic regulation of blood volume occurs predominantly through fluid extravasation from the splenic circulation into lymphatic reservoirs; this is controlled by direct modulation of splenic pre- and postcapillary resistance by established physiologic agents such as atrial natriuretic peptide (ANP), nitric oxide (NO), and adrenomedullin (ADM). In addition to physiologic fluid regulation, splenic extravasation is a key factor in the inability to maintain adequate intravascular volume in septic shock. The spleen also controls renal microvascular tone through reflex activation of the splenic afferent and renal sympathetic nerves. This splenorenal reflex not only contributes to the physiologic regulation of blood pressure, but also contributes to the cardiovascular dysregulation associated with both septic shock and portal hypertension. In septic shock, the splenorenal reflex protectively limits splenic extravasation and potentially promotes renal sodium and water reabsorption and release of the vasoconstrictor angiotensin II; this function is eventually overwhelmed as shock progresses. In portal hypertension, on the other hand, the splenorenal reflex-mediated reduction in renal vascular conductance exacerbates sodium and water retention in the kidneys and may eventually contribute to renal dysfunction. Preliminary evidence suggests that the spleen also may play a role in the hemodynamic complications of portal hypertension via neurohormonal modulation of the mesenteric vascular bed. Lastly, the spleen itself may be a source of a vasoactive factor.

Systemic and renal oxidative stress in the pathogenesis of hypertension: modulation of long-term control of arterial blood pressure by resveratrol

Hypertension affects over 25% of the global population and is associated with grave and often fatal complications that affect many organ systems. Although great advancements have been made in the clinical assessment and treatment of hypertension, the cause of hypertension in over 90% of these patients is unknown, which hampers the development of targeted and more effective treatment. The etiology of hypertension involves multiple pathological processes and organ systems, however one unifying feature of all of these contributing factors is oxidative stress. Once the bodys natural anti-oxidant defense mechanisms are overwhelmed, reactive oxygen species (ROS) begin to accumulate in the tissues. ROS play important roles in normal regulation of many physiological processes, however in excess they are detrimental and cause widespread cell and tissue damage as well as derangements in many physiological processes. Thus, control of oxidative stress has become an attractive target for pharmacotherapy to prevent and manage hypertension. Resveratrol (trans-3,5,4′-Trihydroxystilbene) is a naturally occurring polyphenol which has anti-oxidant effects in vivo. Many studies have shown anti-hypertensive effects of resveratrol in different pre-clinical models of hypertension, via a multitude of mechanisms that include its function as an anti-oxidant. However, results have been mixed and in some cases resveratrol has no effect on blood pressure. This may be due to the heavy emphasis on peripheral vasodilator effects of resveratrol and virtually no investigation of its potential renal effects. This is particularly troubling in the arena of hypertension, where it is well known and accepted that the kidney plays an essential role in the long term regulation of arterial pressure and a vital role in the initiation, development and maintenance of chronic hypertension. It is thus the focus of this review to discuss the potential of resveratrol as an anti-hypertensive treatment via amelioration of oxidative stress within the framework of the fundamental physiological principles of long term regulation of arterial blood pressure.

Splenorenal reflex modulates renal blood flow in the rat

We have previously shown that the splenorenal reflex controls renin release through splenic afferent and renal sympathetic nerves. We proposed that this reflex would also affect renal blood flow (RBF). RBF was measured in male Long Evans rats using transit‐time flow probes. There were no significant differences between any of the experimental groups with respect to baseline values of RBF (8.9 ± 0.4 ml min−1, n= 25) or mean arterial pressure (MAP, 98.7 ± 2.5 mmHg, n= 25). Splenic venous pressure was selectively raised (from 7.9 ± 0.6 to 21.6 ± 0.3 mmHg, n= 25) in anaesthetized rats by partial ligation of the splenic vein. This caused an immediate fall in RBF (−2.1 ± 0.2 ml min−1, n= 7) and in MAP (−12.4 ± 2.8 mmHg, n= 7). The fall in RBF, but not the fall in blood pressure, was attenuated by renal denervation (ΔRBF: − 0.7 ± 0.1 ml min−1, n= 6), splenic denervation (ΔRBF: −0.8 ± 0.1 ml min−1, n= 6) and close renal arterial injection of the α1‐adrenergic blocker phenoxybenzamine (12.5 μg; ΔRBF: −0.8 ± 0.1 ml min−1, n= 6). Renal conductance fell only in the intact control group, i.e. the residual fall in RBF in the denervated and phenoxybenzamine‐treated animals could be attributed to the fall in MAP. We also showed that splenic vein occlusion increased both splenic afferent (from 3.0 ± 0.3 to 6.6 ± 0.6 spikes s−1, n= 5) and renal efferent (from 24.8 ± 2.0 to 50.2 ± 4.9 spikes s−1, n= 9) nerve activity. We conclude that obstruction to splenic venous outflow, such as would occur in portal hypertension, initiates increased splenic afferent nerve activity and renal vasoconstriction through the splenorenal reflex, as well as a fall in blood pressure. We propose that this contributes to the renal and cardiovascular dysfunction observed in portal hypertension.

Everything we always wanted to know about furosemide but were afraid to ask

Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemides effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion.

Role of STAT3 in angiotensin II-induced hypertension and cardiac remodeling revealed by mice lacking STAT3 serine 727 phosphorylation

STAT3 is involved in protection of the heart provided by ischemic preconditioning. However, the role of this transcription factor in the heart in chronic stresses such as hypertension has not been defined. We assessed whether STAT3 is important in hypertension-induced cardiac remodeling using mice with reduced STAT3 activity due to a S727A mutation (SA/SA). Wild type (WT) and SA/SA mice received angiotensin (ANG) II or saline for 17 days. ANG II increased mean arterial and systolic pressure in SA/SA and WT mice, but cardiac levels of cytokines associated with heart failure were increased less in SA/SA mice. Unlike WT mice, hearts of SA/SA mice showed signs of developing systolic dysfunction as evidenced by reduction in ejection fraction and fractional shortening. In the left ventricle of both WT and SA/SA mice, ANG II induced fibrosis. However, fibrosis in SA/SA mice appeared more extensive and was associated with loss of myocytes. Cardiac hypertrophy as indexed by heart to body weight ratio and left ventricular anterior wall dimension during diastole was greater in WT mice. In WT+ANG II mice there was an increase in the mass of individual myofibrils. In contrast, cardiac myocytes of SA/SA+ANG II mice showed a loss in myofibrils and myofibrillar mass density was decreased during ANG II infusion. Our findings reveal that STAT3 transcriptional activity is important for normal cardiac myocyte myofibril morphology. Loss of STAT3 may impair cardiac function in the hypertensive heart due to defective myofibrillar structure and remodeling that may lead to heart failure.

A novel complex I inhibitor protects against hypertension-induced left ventricular hypertrophy

Since left ventricular hypertrophy (LVH) increases the susceptibility for the development of other cardiac conditions, pharmacotherapy that mitigates pathological cardiac remodeling may prove to be beneficial in patients with LVH. Previous work has shown that the activation of the energy-sensing kinase AMP-activated protein kinase (AMPK) can inhibit some of the molecular mechanisms that are involved in LVH. Of interest, metformin activates AMPK through its inhibition of mitochondrial complex I in the electron transport chain and can prevent LVH induced by pressure overload. However, metformin has additional cellular effects unrelated to AMPK activation, raising questions about whether mitochondrial complex I inhibition is sufficient to reduce LVH. Herein, we characterize the cardiac effects of a novel compound (R118), which is a more potent complex I inhibitor than metformin and is thus used at a much lower concentration. We show that R118 activates AMPK in the cardiomyocyte, inhibits multiple signaling pathways involved in LVH, and prevents Gq protein-coupled receptor agonist-induced prohypertrophic signaling. We also show that in vivo administration of R118 prevents LVH in a mouse model of hypertension, suggesting that R118 can directly modulate the response of the cardiomyocyte to stress. Of importance, we also show that while R118 treatment prevents adaptive remodelling in response to elevated afterload, it does so without compromising systolic function, improves myocardial energetics, and prevents a decline in diastolic function in hypertensive mice. Taken together, our data suggest that inhibition of mitochondrial complex I may be worthy of future investigation for the treatment of LVH.NEW & NOTEWORTHY Inhibition of mitochondrial complex I by R118 reduces left ventricular hypertrophy (LVH) and improves myocardial energetics as well as diastolic function without compromising systolic function. Together, these effects demonstrate the therapeutic potential of complex I inhibitors in the treatment of LVH, even in the presence of persistent hypertension.

Co-administration of resveratrol with doxorubicin in young mice attenuates detrimental late-occurring cardiovascular changes

Aims Doxorubicin (DOX) is among the most effective chemotherapies used in paediatric cancer patients. However, the clinical utility of DOX is offset by its well-known cardiotoxicity, which often does not appear until later in life. Since hypertension significantly increases the risk of late-onset heart failure in childhood cancer survivors, we investigated whether juvenile DOX exposure impairs the ability to adapt to angiotensin II (Ang II)-induced hypertension later in life and tested a treatment that could prevent this. Methods and results Five-week-old male mice were administered a low dose of DOX (4 mg/kg) or saline once a week for 3 weeks and then allowed to recover for 5 weeks. Following the 5-week recovery period, mice were infused with Ang II or saline for 2 weeks. In another cohort, mice were fed chow containing 0.4% resveratrol 1 week before, during, and 1 week after the DOX administrations. One week after the last DOX administration, p38 mitogen-activated protein kinase (MAPK) was activated in hearts of DOX-treated mice demonstrating molecular signs of cardiac stress; yet, there was no change in cardiac function between groups. However, DOX-treated mice failed to develop compensatory cardiac hypertrophy in response to Ang II-induced hypertension later in life. Of importance, mice receiving DOX with resveratrol co-administration displayed normalization in p38 MAPK activation in the heart and a restored capacity for cardiac hypertrophy in response to Ang II-induced hypertension. Conclusion We have developed a juvenile mouse model of DOX-induced cardiotoxicity that displays no immediate overt physiological dysfunction; but, leads to an impaired ability of the heart to adapt to hypertension later in life. We also show that co-administration of resveratrol during DOX treatment was sufficient to normalize molecular markers of cardiotoxicity and restore the ability of the heart to undergo adaptive remodelling in response to hypertension later in life.

Understanding the Two Faces of Low-Salt Intake

Fierce debate has developed whether low-sodium intake, like high-sodium intake, could be associated with adverse outcome. The debate originates in earlier epidemiological studies associating high-sodium intake with high blood pressure and more recent studies demonstrating a higher cardiovascular event rate with both low- and high-sodium intake. This brings into question whether we entirely understand the consequences of high- and (very) low-sodium intake for the systemic hemodynamics, the kidney function, the vascular wall, the immune system, and the brain. Evolutionarily, sodium retention mechanisms in the context of low dietary sodium provided a survival advantage and are highly conserved, exemplified by the renin-angiotensin system. What is the potential for this sodium-retaining mechanism to cause harm? In this paper, we will consider current views on how a sodium load is handled, visiting aspects including the effect of sodium on the vessel wall, the sympathetic nervous system, the brain renin-angiotensin system, the skin as “third compartment” coupling to vascular endothelial growth factor C, and the kidneys. From these perspectives, several mechanisms can be envisioned whereby a low-sodium diet could potentially cause harm, including the renin-angiotensin system and the sympathetic nervous system. Altogether, the uncertainties preclude a unifying model or practical clinical guidance regarding the effects of a low-sodium diet for an individual. There is a very strong need for fundamental and translational studies to enhance the understanding of the potential adverse consequences of low-salt intake as an initial step to facilitate better clinical guidance.