Heringer-Walther, S.

Cardiac phenotype and angiotensin II levels in AT1a, AT 1b, and AT2 receptor single, double, and triple knockouts (Article)

2010-06-01T00:00:00Z

AimsOur aim was to determine the contribution of the three angiotensin (Ang) II receptor subtypes (AT1a, AT1b, AT2) to coronary responsiveness, cardiac histopathology, and tissue Ang II levels using mice deficient for one, two, or all three Ang II receptors.Methods and resultsHearts of knockout mice and their wild-type controls were collected for histochemistry or perfused according to Langendorff, and kidneys were removed to measure tissue Ang II. Ang II dose-dependently decreased coronary flow (CF) and left ventricular systolic pressure (LVSP), and these effects were absent in all genotypes deficient for AT1a, independently of AT1band AT2. The deletion of Ang II receptors had an effect neither on the morphology of medium-sized vessels in the heart nor on the development of fibrosis. However, the lack of both AT1subtypes was associated with atrophic changes in the myocardium, a reduced CF and a reduced LVSP. AT1adeletion alone, independently of the presence or absence of AT1band/or AT2, reduced renal Ang II by 50 despite a five-fold rise of plasma Ang II. AT1bdeletion, on top of AT1adeletion (but not alone), further decreased tissue Ang II, while increasing plasma Ang II. In mice deficient for all three Ang II receptors, renal Ang II was located only extracellularly. Conclusion The lack of both AT1subtypes led to a baseline reduction of CF and LVSP, and the effects of Ang II on CF and LVSP were found to be exclusively mediated via AT1a. The lack of AT1aor AT1bdoes not influence the development or maintenance of normal cardiac morphology, whereas deficiency for both receptors led to atrophic changes in the heart. Renal Ang II levels largely depend on AT1binding of extracellularly generated Ang II, and in the absence of all three Ang II receptors, renal Ang II is only located extracellularly.

Angiotensin-(1-7) stimulates hematopoietic progenitor cells in vitro and in vivo (Article)

2009-06-01T00:00:00Z

Effects of angiotensin (Ang)-(1-7), an AngII metabolite, on bone marrow-derived hematopoietic cells were studied. We identified Ang-(1-7) to stimulate proliferation of human CD34+and mononuclear cells in vitro. Under in vivo conditions, we monitored proliferation and differentiation of human cord blood mononuclear cells in NOD/SCID mice. Ang-(1-7) stimulated differentially human cells in bone marrow and accumulated them in the spleen. The number of HLA-I+and CD34+cells in the bone marrow was increased 42-fold and 600-fold, respectively. These results indicate a decisive impact of Ang-(1-7) on hematopoiesis and its promising therapeutic potential in diseases requiring progenitor stimulation.

Angiotensin-(1-7) and the G protein-coupled receptor Mas are key players in renal inflammation (Article)

2009-04-30T00:00:00Z

Angiotensin (Ang) II mediates pathophysiologial changes in the kidney. Ang-(1-7) by interacting with the G protein-coupled receptor Mas may also have important biological activities. In this study, renal deficiency for Mas diminished renal damage in models of renal insufficiency as unilateral ureteral obstruction and ischemia/reperfusion injury while the infusion of Ang-(1-7) to wild-type mice pronounced the pathological outcome by aggravating the inflammatory response. Mas deficiency inhibited NF-κB activation and thus the elevation of inflammation-stimulating cytokines, while Ang-(1-7) infusion had proinflammatory properties in experimental models of renal failure as well as under basal conditions. The Ang-(1-7)-mediated NF-κB activation was Mas dependent but did not involve Ang II receptors. Therefore, the blockade of the NF-κB-activating properties of the receptor Mas could be a new strategy in the therapy of failing kidney.

Cardiovascular phenotype of mice lacking all three subtypes of angiotensin II receptors (Article)

2008-08-01T00:00:00Z

Angiotensin II activates two distinct receptors, the angiotensin II receptors type 1 (AT1) and type 2 (AT2). In rodents, two AT1subtypes were identified (AT1aand AT1b). To determine receptor-specific functions and possible angiotensin II effects independent of its three known receptors we generated mice deficient in either one of the angiotensin II receptors, in two, or in all three (triple knockouts). Triple knockouts were vital and fertile, but survival was impaired. Hypotension and renal histological abnormalities in triple knockouts were comparable to those in mice lacking both AT1subtypes. All combinations lacking AT1awere distinguished by reduced heart rate. AT1adeletion impaired the in vivo pressor response to angiotensin II bolus injection, whereas deficiency for AT1band/or AT2had no effect. However, the additional lack of AT1bin AT1a-deficient mice further impaired the vasoconstrictive capacity of angiotensin II. Although general vasoconstrictor properties were not changed, angiotensin II failed to alter blood pressure in triple knockouts, indicating that there are no other receptors involved in direct angiotensin II pressor effects. Our data identify mice deficient in all three angiotensin II receptors as an ideal tool to better understand the structure and function of the reninangiotensin system and to search for angiotensin II effects independent of AT1and AT2.

Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: A new target to improve endothelial function (Article)

2007-12-01T00:00:00Z

BACKGROUND: Endothelial dysfunction is an initial step in the pathogenesis of cardiovascular diseases. Since we previously identified the G protein-coupled receptor Mas as a receptor for angiotensin (Ang)-(1-7), a heptapeptide with endothelium-dependent vasorelaxant properties, we investigated whether alterations on the Ang-(1-7)/Mas axis alter endothelial function. RESULTS: Ang-(1-7)-mediated relaxation of murine wild-type mesenteric arteries was equally impaired in both wild-type arteries pretreated with the Ang-(1-7) receptor blocker, A779, and arteries isolated from Mas-deficient mice. Importantly, the response to the endothelium-dependent vasorelaxant, bradykinin (BK), and acetylcholine (ACh) effects were comparably inhibited, while endothelium-independent vessel relaxation by sodium nitroprusside was unaltered in these vessels. Hypothesizing endothelial dysfunction, we proved the in-vivo relevance of the ex-vivo findings investigating mesenteric properties after 1 week of minipump infusion of A779 in wild-type mice. Both BK- and ACh-induced relaxation were significantly impaired in wild-type vessels of pretreated animals. A779-induced impairment of endothelial function was confirmed in vitro, since BK-mediated nitric oxide (NO) release was increased by Ang-(1-7) and blunted by A779 pretreatment in primary human endothelial cell cultures. CONCLUSIONS: Our data highlight a pivotal role for the receptor Mas in preserving normal vascular relaxation. Consequently, Mas agonists arise as a promising tool in the treatment of cardiovascular diseases characterized by endothelial dysfunction.

The angiotensin-(1-7) receptor agonist AVE0991 dominates the circadian rhythm and baroreflex in spontaneously hypertensive rats (Article)

2007-02-01T00:00:00Z

Because we previously suggested the endogenous heptapeptide angiotensin (Ang)-(1-7) to be involved in the improvement of baroreflex sensitivity observed in spontaneously hypertensive rats (SHR), we here investigated the role of the heptapeptide in blood pressure control under physiologic conditions in awake SHR using the first nonpeptide, orally applicable Ang-(1-7) receptor agonist AVE0991 by telemetry. Five weeks after the start of treatment the blood pressure signals (500 Hz) were monitored in 10 untreated and 6 age-matched male SHR treated by AVE0991 for 24 hours (every 2 hours for 10 minutes). The autonomous tone was estimated from the heart rate and blood pressure variability (HRV, BPV) and from the spontaneous baroreceptor sensitivity (BRS). AVE0991 treatment blunted the rodent-characterizing nightly increase in blood pressure and led to pronounced changes in the BPV and HRV parameters during the night in comparison to untreated controls (eg, sdNN: AVE0991 = 8.19 versus control = 11.5 mm Hg; P < 0.001). However, even more significant differences were detected for BRS. Whereas the average slope did not alter, the activation of the baroreflexes (P < 10E-6) and the number of baroreflex fluctuations were reduced dramatically by AVE0991 (P < 10E-5). The data obtained pointed to an abating impact of AVE0991 on the baroreceptor in SHR and to its influence on the circadian rhythm, thus implying a direct involvement of Ang-(1-7) in cardiovascular control.

Accelerated mitochondrial adenosine diphosphate/adenosine triphosphate transport improves hypertension-induced heart disease (Article)

2007-01-01T00:00:00Z

BACKGROUND: Strong evidence suggests that mitochondrial malfunction, which leads to disturbed energy metabolism and stimulated apoptosis, is a linchpin in the induction and manifestation of cardiac failure. An adequate exchange of ATP and ADP over the inner mitochondrial membrane by the adenine nucleotide translocase (ANT) is thereby essential to guarantee the cellular energy supply. METHODS AND RESULTS: To explore the effect of an ameliorated mitochondrial ATP/ADP transportation on cardiac dysfunction, we generated transgenic rats overexpressing ANT1 in the heart (ANT rats) and crossed them with renin-overexpressing rats (REN rats) suffering from hypertension-induced cardiac insufficiency. Cardiac-specific ANT1 overexpression resulted in a higher ATP/ADP transportation and elevated activities of respiratory chain complexes. Increased ANT activity in double-transgenic (ANT/REN) animals did not influence excessive hypertension seen in REN rats. Hypertension-induced cardiac hypertrophy in the REN rats was prevented by parallel ANT1 overexpression, however, and left ventricular function remarkably improved. The ANT1 overexpression led to a reduction in fibrosis and an improvement in cardiac tissue architecture. Consequently, the survival rate of ANT/REN rats was enhanced. Further investigations into the cardioprotective mechanism of ANT1 overexpression revealed improved mitochondrial structure and function and significantly reduced apoptosis in ANT/REN rats, shown by lowered cytosolic/mitochondrial cytochrome c ratio, reduced caspase 3 level, and prevented DNA degradation. CONCLUSIONS: Myocardial ANT1 overexpression protects against hypertension-induced cardiac pathology. Thus, the improvement in mitochondrial function may be a basic principle for new strategies in treating heart disease.