Table 5:
Effects of inhibitors of the renin-angiotensin aldosterone system (RAAS) in animal models of diabetic cardiac fibrosis.
| Agent | Animal model | Effects on cardiac fibrosis, myocardial structure and function | Proposed mechanism of protection | Ref |
|---|---|---|---|---|
| (Pro)renin receptor (PRR) inhibition by RNA interference (RNAi) silencing | STZ-induced type 1 diabetes in rats | Reduction in cardiac collagen I and III, accompanied by improved LV systolic and diastolic function | Inhibition of oxidative stress and ERK signaling, downregulation of TGF-β | [206] |
| Renin inhibition (aliskiren), ACE inhibition (benazepril), AT1R blockade (candesartan) | STZ-induced type I diabetes in rats | Reduction in cardiac fibrosis (partial by candesartan and benazepril alone, complete by aliskiren) and myocyte apoptosis (partial by all three agents) | Inhibition of oxidative stress (partial by candesartan and benazepril alone, complete by aliskiren) | [193] |
| ACE inhibition (ramipril) | STZ- and high-fat diet- induced type 2 diabetes in rats | Reduction in perivascular and interstitial fibrosis and cardiac hypertrophy | N/A | [474] |
| AT1R blockade (irbesartan) | STZ-induced type 1 diabetes in rats | Reduction in cardiac fibrosis and cardiac remodeling | Downregulation of TGF-β/Smad2/3 pathway | [394] |
| AT1R blockade (telmisartan) | STZ-induced type 1 diabetes in rats | Reduction in cardiac fibrosis and improvement of cardiac function | Activation of PPARδ/STAT3/CTGF/MMP-9 pathway | [396] |
| AT1R blockade (valsartan) | KK-Ay mice with diabetic nephropathy | Reduction in cardiac fibrosis, (suggested by decreased deposition of collagen IV and fibronectin) | Attributed to downregulation of miR-21 | [204] |
| AT1R blockade (losartan) | Rats fed a high-fat diet | Attenuated collagen I and III synthesis | Attributed to disruption of TGF-β1/Smad3. | [213] |
| AT1R blockade (irbesartan) | STZ- and high-calorie diet-induced type 2 diabetes in rats | Attenuated cardiac collagen I and collagen III levels, decreased ratio of collagen I/collagen III, and reduced cardiac hypertrophy | Attributed to inhibition of the AGE-RAGE pathway and to alterations in MMP/TIMP expression profile. | [395] |
| Aldosterone receptor antagonism (spironolactone) | STZ-induced type 1 diabetes in rats | Reduction in cardiac fibrosis and hypertrophy | Reduction in oxidative stress, attenuated inflammation and reduced mitochondrial dysfunction | [397] |
| Ang-(1–7) | db/db mice | Reduction in cardiac fibrosis, hypertrophy and apoptosis. Improvement in LV systolic function | Attenuation of inflammation, oxidative stress, lipid accumulation | [200] |
| Ang-(1–7) | db/db mice | Reduction in cardiac fibrosis, hypertrophy. Improvement in LV diastolic function | Reduction in inflammation and cardiac lipotoxicity | [477] |
| AT1R blockade (telmisartan)/neprilysin inhibition (thiorphan) | STZ-induced type 1 diabetes in rats | Reduction in cardiac fibrosis and apoptosis | Reduction in inflammation and histone acetylation | [307] |
| AT1R blockade (valsartan)/neprilysin inhibition (sacubitril) | STZ-induced type 1 diabetes in mice with reperfused myocardial infarction | Reduction in cardiac fibrosis, accompanied by improved LV systolic function | Attributed to suppression of TGF-β | [478] |