Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition

Wal, R. M. A. van de; Plokker, H.W. Thijs; Lok, Dirk J.; Boomsma, Frans; Horst, F.A.L. van der; Veldhuisen, D.J. van; Gilst, Wiek H. van; Voors, A.A.

doi:10.1016/j.ijcard.2005.02.016

Cited by 120 publications

(73 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the above-referenced human study (30), diabetic patients who had elevated iAng II levels were on ACE-inhibitor therapy. In the latter case, a rise in Ang II levels could be attributed to an "ACE-escape" phenomenon, which is believed to occur after prolonged treatment with ACE inhibitors (34). In the present study, the lack of reduction in iAng II levels after only 1 week of ACE-inhibitor treatment strongly suggests an ACE-independent mechanism of iAng II synthesis, corroborating in vitro observations.…”

Section: Discussionsupporting

confidence: 87%

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Singh

Khode³

et al. 2008

Diabetes

293

239

View full text Add to dashboard Cite

OBJECTIVE— Many of the effects of angiotensin (Ang) II are mediated through specific plasma membrane receptors. However, Ang II also elicits biological effects from the interior of the cell (intracrine), some of which are not inhibited by Ang receptor blockers (ARBs). Recent in vitro studies have identified high glucose as a potent stimulus for the intracellular synthesis of Ang II, the production of which is mainly chymase dependent. In the present study, we determined whether hyperglycemia activates the cardiac intracellular renin-Ang system (RAS) in vivo and whether ARBs, ACE, or renin inhibitors block synthesis and effects of intracellular Ang II (iAng II). RESEARCH DESIGN AND METHODS— Diabetes was induced in adult male rats by streptozotocin. Diabetic rats were treated with insulin, candesartan (ARB), benazepril (ACE inhibitor), or aliskiren (renin inhibitor). RESULTS— One week of diabetes significantly increased iAng II levels in cardiac myocytes, which were not normalized by candesartan, suggesting that Ang II was synthesized intracellularly, not internalized through AT 1 receptor. Increased intracellular levels of Ang II, angiotensinogen, and renin were observed by confocal microscopy. iAng II synthesis was blocked by aliskiren but not by benazepril. Diabetes-induced superoxide production and cardiac fibrosis were partially inhibited by candesartan and benazepril, whereas aliskiren produced complete inhibition. Myocyte apoptosis was partially inhibited by all three agents. CONCLUSIONS— Diabetes activates the cardiac intracellular RAS, which increases oxidative stress and cardiac fibrosis. Renin inhibition has a more pronounced effect than ARBs and ACE inhibitors on these diabetes complications and may be clinically more efficacious.

show abstract

Section: Discussionsupporting

confidence: 87%

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Singh

Khode³

et al. 2008

Diabetes

293

239

View full text Add to dashboard Cite

show abstract

“…Moreover, cardiac remodelling occurs in response to activation of the reninangiotensin-aldosterone system. It has been reported that the plasma Ang II concentration is higher in patients with CHF compared to healthy subjects (16). The present study demonstrated that the plasma Ang II level increased gradually dependent on the severity of heart failure.…”

Section: Discussionsupporting

confidence: 69%

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Yang

Ma²,

Tan³

et al. 2010

Int J Mol Med

View full text Add to dashboard Cite

Abstract. The angiotensin (Ang) II/Ang II receptor (ATR)-associated calcium signaling pathway is the major cause of ventricular remodelling in patients with congestive heart failure (CHF). However, the calcium-regulated proteinases responsible for Ang II-induced remodelling are not well understood. We investigated the profiles of the Ang II/ ATR/calpain/calcineurin (CaN) pathway in human failing heart. We measured both the plasma and cardiac levels of Ang II and cardiac mRNA expression of ATR in 39 patients with CHF and 38 healthy controls. Importantly, protein expression of calpains, cleavage of cain/cabin1 and activity of CaN were tested. Both plasma and cardiac levels of Ang II were significantly increased in patients with CHF (both p<0.01), and the plasma Ang II concentration was closely correlated with the parameters of ventricular remodelling (r=±0.29-0.65, p<0.05 or <0.01). In addition, the cardiac level of AT1R but not AT2R was significantly upregulated in mild failing hearts (p<0.05) but dramatically downregulated in severe failing ones (p<0.01). CHF was associated with a marked upregulation of calpains, an increased cleavage of cain/cabin1, and the activation of CaN in the failing ventricular tissue. In patients with CHF, calpain upregulation was associated with an increase in cleavage of cain/cabin1 and the activation of CaN, indicating that these changes in calciumregulated proteinases contribute to Ang II-induced cardiac remodelling.

show abstract

“…As a first step toward understanding the mechanisms that mediate the adverse vascular effects of aldosterone, we began by exploring the effect of aldosterone in the mouse wire carotid injury model, a reproducible method to study these specific responses to endothelial injury (27)(28)(29)(30)(31)(32). Aldosterone was infused at a dose that increased circulating aldosterone concentrations to levels consistent with what is found in patients with heart failure and atherosclerosis (33,34) without altering systolic blood pressure or animal weight (Supplemental Table 1; supplemental material available online with this article; doi:10.1172/JCI40205DS1). Vascular injury resulted in increased medial SMC proliferation, which was significantly augmented by low-dose aldosterone infusion (Supplemental Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Placental growth factor mediates aldosterone-dependent vascular injury in mice

Jaffe¹,

Newfell²,

Aronovitz³

et al. 2010

J. Clin. Invest.

View full text Add to dashboard Cite

Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition

Cited by 120 publications

References 32 publications

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Intracellular Angiotensin II Production in Diabetic Rats Is Correlated With Cardiomyocyte Apoptosis, Oxidative Stress, and Cardiac Fibrosis

Increased expression of calpain and elevated activity of calcineurin in the myocardium of patients with congestive heart failure

Placental growth factor mediates aldosterone-dependent vascular injury in mice

Contact Info

Product

Resources

About