The mechanotransduction of blood pressure Ehmke, Heimo
Science (American Association for the Advancement of Science),
10/2018, Letnik:
362, Številka:
6413
Journal Article
Recenzirano
Two stretch-activated channels in arteries could be targets for some types of heart failure
The arterial baroreceptor reflex is the most important mechanism for minimizing short-term arterial blood ...pressure fluctuations (
1
). In situations of sudden blood pressure drops, the baroreceptor reflex accelerates heart rate, increases cardiac contractility, and induces vasoconstriction. Conversely, sudden increases in blood pressure trigger the opposite response. The autonomic nervous system mediates these physiological reactions. Patients with baroreceptor reflex malfunctions typically suffer from orthostatic hypotension, a severe decrease in blood pressure that occurs when standing up, which leads to dizziness or even fainting (
2
). However, how blood pressure changes are converted into electrical signals for neurotransmission has remained a puzzle. On page 464 of this issue, Zeng
et al.
(
3
) show that the mechanosensitive ion channels PIEZO1 and PIEZO2 are transducers of blood pressure in the sensory neurons of the autonomic nervous system that trigger the baroreceptor reflex. Identifying the molecular players of this response may help clarify the role of arterial baroreceptors in maintaining normotension and help develop new drugs for the treatment of heart failure.
Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by hemodynamic injury. Inflammation also plays an important role in the pathophysiology and ...contributes to the deleterious consequences of this disease. Cells of the innate immune system including monocyte/macrophages and dendritic cells can promote blood pressure elevation via effects mostly on kidney and vascular function. Moreover, convincing evidence shows that T and B cells from the adaptive immune system are involved in hypertension and hypertensive end-organ damage. Skin monocyte/macrophages, regulatory T cells, natural killer T cells, and myeloid-derived suppressor cells have been shown to exert blood pressure controlling effects. Sodium intake is undoubtedly indispensable for normal body function but can be detrimental when taken in excess of dietary requirements. Sodium levels also modulate the function of monocyte/macrophages, dendritic cells, and different T cell subsets. Some of these effects are mediated by changes in the microbiome and metabolome that can be found after high salt intake. Modulation of the immune response can reduce severity of blood pressure elevation and hypertensive end-organ damage in several animal models. The purpose of this review is to briefly summarize recent advances in immunity and hypertension as well as hypertensive end-organ damage.
Salt, inflammation, IL‐17 and hypertension Wenzel, Ulrich O; Bode, Marlies; Kurts, Christian ...
British journal of pharmacology,
June 2019, Letnik:
176, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Traditionally, arterial hypertension and subsequent end‐organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the ...deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4+ T cells into TH17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease.
Linked Articles
This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc
Introduction Ventricular unloading during prolonged bed rest, mechanical circulatory support or microgravity has repeatedly been linked to potentially life-threatening arrhythmias. It is unresolved, ...whether this arrhythmic phenotype is caused by the reduction in cardiac workload or rather by underlying diseases or external stimuli. We hypothesized that the reduction in cardiac workload alone is sufficient to impair ventricular repolarization and to induce arrhythmias in hearts. Methods Rat hearts were unloaded using the heterotopic heart transplantation. The ECG of unloaded and of control hearts were telemetrically recorded over 56 days resulting in >5 × 10 6 cardiac cycles in each heart. Long-term electrical remodeling was analyzed using a novel semi-automatic arrhythmia detection algorithm. Results 56 days of unloading reduced left ventricular weight by approximately 50%. While unloading did not affect average HRs, it markedly prolonged the QT interval by approximately 66% and induced a median tenfold increase in the incidence of ventricular arrhythmias in comparison to control hearts. Conclusion The current study provides direct evidence that the previously reported hypertrophic phenotype of repolarization during cardiac unloading translates into an impaired ventricular repolarization and ventricular arrhythmias in vivo . This supports the concept that the reduction in cardiac workload is a causal driver of the development of arrhythmias during ventricular unloading.
In cardiovascular research, several mouse strains with differing genetic backgrounds are used to investigate mechanisms leading to and sustaining ventricular arrhythmias. The genetic background has ...been shown to affect the studied phenotype in other research fields. Surprisingly little is known about potential strain-specific susceptibilities towards ventricular arrhythmias in vivo. Here, we hypothesized that inter-strain differences reported in the responsiveness of the β-adrenergic pathway, which is relevant for the development of arrhythmias, translate into a strain-specific vulnerability. To test this hypothesis, we characterized responses to β-adrenergic blockade (metoprolol) and β-adrenergic stimulation (isoproterenol) in 4 mouse strains commonly employed in cardiovascular research (Balb/c, BS, C57Bl/6 and FVB) using telemetric ECG recordings. We report pronounced differences in the electrical vulnerability following isoproterenol: Balb/c mice developed the highest number and the most complex arrhythmias while BS mice were protected. Balb/c mice, therefore, seem to be the background of choice for experiments requiring the occurrence of arrhythmias while BS mice may give insight into electrical stability. Arrhythmias did not correlate with the basal β-adrenergic tone, with the response to β-adrenergic stimulation or with the absolute heart rates during β-adrenergic stimulation. Thus, genetic factors dominate the susceptibility to ventricular arrhythmias in this model of β-adrenergic stimulation.
A key finding supporting a causal role of the immune system in the pathogenesis of hypertension is the observation that
knockout mice on a C57Bl/6J background (B6.Rag1
), which lack functional B and ...T cells, develop a much milder hypertensive response to Ang II (angiotensin II) than control C57Bl/6J mice. Here, we report that we never observed any Ang II resistance of B6.Rag1
mice purchased directly from the Jackson Laboratory as early as 2009. B6.Rag1
mice displayed nearly identical blood pressure increases monitored via radiotelemetry and hypertensive end-organ damage in response to different doses of Ang II and different levels of salt intake (0.02%, 0.3%, and 3% NaCl diet). Similarly, restoration of T-cell immunity by adoptive cell transfer did not affect the blood pressure response to Ang II in B6.Rag1
mice. Full development of the hypertension-resistant phenotype in B6.Rag1
mice appears to depend on the action of yet unidentified nongenetic modifiers in addition to the absence of functional T cells.
The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and ...with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.
High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca2+-activated chloride ...currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstriction-inducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.
Key points
The adrenal hormone aldosterone can stimulate K+ secretion during hyperkalaemia and Na+ reabsorption during hypovolaemia in the kidney.
Angiotensin II is thought to switch the ...physiological mode of action from K+ excretion towards Na+ retention, but how the regulation is achieved when angiotensin II levels are suppressed by high Na+ intake remains unknown.
We report that both dietary K+ depletion and dietary K+ loading provoke renal Na+ retention and increase blood pressure in Na+ replete mice, but these occur through different renal kinase signalling and Na+ transport pathways.
An angiotensin II‐ and aldosterone‐independent activation of the sodium‐chloride cotransporter NCC contributes to the blood pressure increase induced by K+ depletion, whereas the hypertensive response to K+ loading is dependent on neither aldosterone nor Na+ transport via the epithelial sodium channel ENaC.
These findings imply a major impact of K+ homeostasis on renal Na+ handling in the Na+ replete state and suggest a mechanism for the hypertensive effect of the Western diet (high Na+ and low K+) in humans.
A network of kinases, including WNKs, SPAK and Sgk1, is critical for the independent regulation of K+ and Na+ transport in the distal nephron. Angiotensin II is thought to act as a key hormone in orchestrating these kinases to switch from K+ secretion during hyperkalaemia to Na+ reabsorption during intravascular volume depletion, thus keeping disturbances in electrolyte and blood pressure homeostasis at a minimum. It remains unclear, however, how K+ and Na+ transport are regulated during a high Na+ intake, which is associated with suppressed angiotensin II levels and a high distal tubular Na+ load. We therefore investigated the integrated blood pressure, renal, hormonal and gene and protein expression responses to large changes of K+ intake in Na+ replete mice. Both low and high K+ intake increased blood pressure and caused Na+ retention. Low K+ intake was accompanied by an upregulation of the sodium‐chloride cotransporter (NCC) and its activating kinase SPAK, and inhibition of NCC normalized blood pressure. Renal responses were unaffected by angiotensin AT1 receptor antagonism, indicating that low K+ intake activates the distal nephron by an angiotensin‐independent mode of action. High K+ intake was associated with elevated plasma aldosterone concentrations and an upregulation of the epithelial sodium channel (ENaC) and its activating kinase Sgk1. Surprisingly, high K+ intake increased blood pressure even during ENaC or mineralocorticoid receptor antagonism, suggesting the contribution of aldosterone‐independent mechanisms. These findings show that in a Na+ replete state, changes in K+ intake induce specific molecular and functional adaptations in the distal nephron that cause a functional coupling of renal K+ and Na+ handling, resulting in Na+ retention and high blood pressure when K+ intake is either restricted or excessively increased.
Abstract
HCN channels underlie the depolarizing funny current (I
f
) that contributes importantly to cardiac pacemaking. I
f
is upregulated in failing and infarcted hearts, but its implication in ...disease mechanisms remained unresolved. We generated transgenic
mice
(
HCN4
tg/wt
) to assess functional consequences of
HCN4
overexpression-mediated I
f
increase in cardiomyocytes to levels observed in
human
heart failure.
HCN4
tg/wt
animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. I
f
augmentation induces a diastolic Na
+
influx shifting the Na
+
/Ca
2+
exchanger equilibrium towards ‘reverse mode’ leading to increased Ca
2+
i
. Changed Ca
2+
homeostasis results in significantly higher systolic Ca
2+
i
transients and stimulates apoptosis. Pharmacological inhibition of I
f
prevents the rise of Ca
2+
i
and protects from ventricular remodeling. Here we report that augmented myocardial I
f
alters intracellular Ca
2+
homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I
f
per se
may constitute a therapeutic mechanism to prevent cardiomyopathy.
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