Renin-angiotensin System and Cardiovascular Diseases- Focusing on Mechanisms of Structural and Electrical Remodelings in Atrial Fibrillation and Pharmacological Approach
Date Issued
2006
Date
2006
Author(s)
DOI
zh-TW
Abstract
The aim of the present doctoral thesis is to investigate the detailed molecular mechanism by which angiotensin II (AngII) is involved in the pathegenesis of atrial fibrillation (AF). Recently, it has been shown that local atrial rennin-angiotensin system (RAS) is activated with increased tissue AngII level during AF. AngII activates the downstream mitogen-activated protein kinase pathway (MAPK) signaling pathways, resulting in atrial structural remodeling. AngII is also involved in atrial electrical remodeling, and it has also been shown that blockage of endogenous AngII prevents rapid-pacing induced shortening of atrial effective refractory period (AERP).
In our previous study, we first demonstrated the genetic association between RAS genetic variations and the development of AF. In the present study, we further increased the sample size of our genetic association study to more than 2 fold, and have found more significant results. We also showed that RAS genetic variations and gene-gene interactions among RAS genes were also associated with the development of various cardiovascular diseases, including hypertension and coronary artery disease, in addition to AF. Because the molecular mechanisms by which AngII is involved in the pathogenesis of hypertension or coronary artery disease are well known, the following study subjects were focusing on the molecular mechanisms by which AngII is involved in the pathogenesis of AF, with emphases on the structural and electrical remodelings.
Regarding AngII and structural remodeling, we used a rapid-pacing porcine AF model. AF was induced by atrial pacing at 600/min in adult pigs. Significant structural and inflammatory changes were noted in the AF pigs. Although atrial tissue angiotensin II level was elevated in the AF pigs, the MAPK pathways were not activated. However, signal transducers and activators of transcription-1 (STAT1) and STAT3 were activated with increased STAT3 nuclear translocation in the AF pigs. Membrane translocation and activation of Rac1 was also noted. Furthermore, in cultured atrial myocytes and fibroblasts, angiotensin II activated STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant negative Rac1, losartan and simvastatin. We found that the STATs pathways, but not the MAPKs, were activated by angiotensin II and might contribute to structural and inflammatory changes in AF. The activation of STAT3 was dependent on Rac1 and was blocked by losartan and simvastatin.
Regarding AngII and electrical remodeling, we investigated whether AngII modulates L-type calcium channel (LCC) current through transcriptional regulation, using a murine atrial HL-1 cells model. AngII increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient. AngII significantly increased promoter activity of LCC α1C subunit gene in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE)(-1853 to –1845) was an important cis-element in Ang II-induced LCC α1C subunit gene expression. AngII induced serine 133 phosphorylation of CRE binding protein (CREB), binding of CREB to CRE, and increase of LCC α1C subunit gene promoter activity through a protein kinase C (PKC)/NADPH oxidase/reactive oxygen species (ROS) dependent pathway, which was blocked by the AngII type 1 receptor blocker losartan and the antioxidant simvastatin. In summary, Ang II increases LCC α1C subunit expression, LCC current density, and amplitude of the calcium transient in atrial myocytes. AngII-induced LCC α1C subunit expression was PKC-, ROS-, and CREB-dependent, and was blocked by losartan and simvastatin.
Why local atrial tissue angiotensin II (AngII) production is up-regulated during atrial fibrillation (AF)? It is possible that atrial myocytes express all the components of renin-angiotensin system (RAS), and AF or rapid depolarization per se could increase AngII production by up-regulating the expressions of components of RAS. Again, we used porcine and cellular models to prove this hypothesis. In the cell model, AF was simulated in the cultured murine atrial HL-1 cells by rapid field pacing (RES)(1.0 V/cm, 10 Hz). AngII concentration was measured by ELISA, and expressions of angiotensin converting enzyme (ACE), chymase, angiotensinogen (AGT), renin, AngII type 1 receptor (AT1R) and type 2 receptor (AT2R) were measured by immnunoblotting. In the porcine model, atrial tissue AngII, ACE, chymase and AGT were up-regulated in the AF pigs, but renin was down-regulated. AT1R was up-regulated in the left atria, but down-regulated in the right atria. AT2R was up-regulated in both left atria and right atria. In the cellular model, RES induced a similar pattern of expressions of RAS components, and increased AngII concentrations in the mediums and cellular extracts. RES induced AngII production was attenuated by ACEI Enalapril and chymase inhibitor chymostatin. These results suggest that combination of ACEI and chymase inhibitor prevents rapid-depolarization induced AngII production and atrial structural remodeling.
Regarding clinical studies, to evaluate whether echocardiography could be used to evaluate atrial volume and function that may be related to atrial structural remodeling, we first designed a study to evaluate the left atrial (LA) volume, and LA systolic (contractile) and diastolic (expansion) functions in different stages of hypertension with or without atrial fibrillation, as well as the effects of good blood pressure control. This was a prospective observational study. Individuals including 22 normotensive controls, 23 patients with mild hypertension (MH), 20 with severe hypertension (SH), and 17 with both hypertension and paroxysmal atrial fibrillation (AH) were recruited for paired echocardiography studies at baseline and 6 months after medical control of hypertension. We found that with increasing severity of hypertension, LV diastolic function deteriorated progressively from controls, MH, SH, to AH patients. LA expansion index was reduced in parallel. LA expansion index was correlated positively with LV E’/A’ ratio and inversely with LV E/E’ ratio. Significant improvement of LV diastolic function and LA expansion index preceded the reduction of LA volume after 6 months of effective blood pressure control. In summary, with progressive LV diastolic dysfunction in different stages of hypertension, there was a corresponding deterioration in LA expansion or diastolic function, which preceded changes in LA volume and LA contractile function.
Recently there is increasing evidence that AF is an inflammatory disease. It has also been shown that statin is a potent anti-inflammatory agent. Furthermore, in the above studies, we have showed that statin blocked AngII signaling pathways, which play important roles in atrial structural and electrical remodeling. Therefore, we hypothesized that statin therapy may provide an effective treatment strategy for AF. We conducted a prospective randomzed clinical study to test the efficacy of atorvastatin in the treatment of paroxysmal AF (PAF). We chose patients who have received implantation of a pacemaker. By pacemaker interrogation, we could accurately detect the first attack of AF to see the effect of atorvastatin to prevent AF attack. Fifty-two patients (23 males, 70±13 years old) were randomized to the statin group and 54 (25 males, 72±13 years old) to the control group. Around 70 % of the patients had SSS and the remaining AVB. Around 75 % of the patients had underwent implantation of a dual chamber pacemaker (DDD[R]), and the remaining single chamber PM (AAI[R]). Three patients did not complete the follow-up and the other patients completed the followed-up for one year. Significant atrial high rate episode (AHE)(rate>180/min and duration≧10 min) occurred in 3 of 50 patients (6.0%) in the statin group, and 10 of 53 patients (18.9%)(OR=0.27; 95% confidence interval [CI] 0.05-0.96, p=0.03) in the control group. Patients in the non-statin group were more likely to develop significant AHE that those in the statin group (log-rank p=0.028). The present study clearly and accurately demonstrated the efficacy of atorvastatin to prevent the occurrence of AF in patients with bradycardia. The possible molecular mechanisms warrant further studies.
In conclusions, the present doctoral thesis combined genetic association studies, molecular studies and clinical studies to demonstrate how AngII is involved in the pathogeneses of atrial structural and electrical remodeling, which are important substrates of AF. We first showed the association between RAS genetic variants and the development of AF. Second, we further investigated the possible molecular mechanisms by which AngII is involved in the pathogeneses of atrial structural and electrical remodelings. Third, we found that echocardiography was a useful tool to non-invasively evaluate atrial volume and function, which could serve as a clinical surrogate to represent atrial structural remodeling. Finally, we performed a prospective and randomized clinical trial showing a decrease of AF by statin, which has been shown to block AngII signaling pathways in the former basic molecular studies.
Subjects
腎素血管張力素系統
心房纖維顫動
Renin-angiotensin system
atrial fibrillation
SDGs
Type
text
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