**3. Pharmacology on vascular remodeling**

#### **3.1. New drugs**

LCZ696 is the first of a new class of drugs that simultaneously block angiotensin 1 receptor blocker (ARB) and neprilysin or neutral endopeptidase protein (NEP); hence, they are referred to with the acronym ARNI [22].

This complex system results in multiple effects on the cardiovascular system. In the first instance, according to different experiments, LCZ696 can increase the half-life of BNP through the initiation of NEP, managing to increase natriuresis and vasodilation through activation of the NPRA receptor. On the other hand, the blockade of AT1R can decrease fibrosis, induce vasodilation, reduce the retention of sodium and water, lower blood pressure, and other effects [23].

The most important clinical study that demonstrated the reduction of cardiovascular morbidity and mortality in patients with heart failure was the PARADIGM-HF study, which showed a clear benefit in patients who were in the branch receiving LCZ696. However, studies in experimental animals and pathophysiological analyses are scarce. Thus, the precise mechanism by which LCZ696 reduces cardiovascular mortality remains unclear. Some authors have proposed different hypotheses: (1) a sustained increase in natriuretic peptides by inhibition of NEP, (2) a direct hemodynamic effect that reduces stress on the left ventricular wall, (3) a reduction in arrhythmias and by a reduction in fibrosis or myocardial hypertrophy, and (4) an improvement of regional myocardial perfusion [4].

Previously, drug-intervention studies in this model have shown that some antihypertensive treatments, with candesartan, telmisartan, and losartan, not only lower blood pressure but also cause an improvement in redox balance and regression of structural changes in resistance arteries, although not a regeneration of the endothelium. In other words, reversing adverse effects associated with hypertension does not improve the normal structure and function of endothelial cells [8, 9].

Within the inflammatory cascades activated in this experimental model, we found that the determinant of the previously evidenced changes is that of the IL-6 receptor. Two different forms of IL-6 cell receptors have been described: an 80 kDa ligand-binding chain, known as IL-6R (IL-6Ra, CD126), and a 130 kDa signal transduction chain, gp130 (IL-6Rb, CD130). Gp130 is present in many places and situations; in contrast, IL-6R shows a more limited expression pattern [24].

In a recent publication of our group, it can be concluded that LCZ696 can reverse the changes associated with vascular remodeling, even more important than just blocking AT1R. The proposed pathway to demonstrate this finding was through the inhibition of the intracellular cascade of STAT3/JAK in intimate relation with IL-6R alpha, thus demonstrating an intrinsic anti-inflammatory effect. In addition, from the inhibition of STAT3, LCZ696 managed to significantly increase the amount of EPC at the vascular level, thus mediating endothelial repair [25].

On the other hand, NEP and ACE2 probably induce the conversion of angiotensin II in different intermediate metabolites, such as angiotensin 1-7 (Ang 1-7), which produces antagonistic effects to angiotensin II by MAS1R. The intracellular cascade of MAS1R, by MAPK/ERK, produces a fundamental effect, namely, the production of VEGF and its two receptors, VEGFR1 and VEGFR2. From this mechanism, the endothelium could be repaired and/or replaced, favoring the maturation of circulating EPCs on resident EPCs at the endothelial level. MAS1R

**Figure 3.** The phytopathological mechanisms proposed in our work are summarized in this image. The dual blocking of NEP/AT1R by LCZ696 could reduce the expression and phosphorylation of STAT3 through JAK, either by blocking AT1R, reducing oxidative stress, or controlling systolic blood pressure. The reduction of STAT3 produced a decrease in the inflammatory transcription factors in the nucleus and a release of hsCRP in the blood circulation, which produces an increasing docking of the alpha subunit of IL-6R toward the membrane. On the other hand, NEP and ACE2 probably induce the conversion of angiotensin II in different intermediate metabolites, such as angiotensin 1-7 (Ang 1-7), which produces antagonistic effects to angiotensin II by MAS1R. The intracellular cascade of MAS1R, by MAPK/ERK, produces a fundamental effect, namely, the production of VEGF and its two receptors: VEGFR1 and 2. From this mechanism, the endothelium could be repaired and/or replaced, favoring the maturation of circulating EPCs on resident EPCs at the

Role of Insulin Resistance in Vascular Inflammation http://dx.doi.org/10.5772/intechopen.77287 83

In conclusion, we postulate that LCZ696, by MAS1R activation, is not only able to improve endothelial function but also able to repair the endothelium, and this probably allows for improved functionality of the entire cardiovascular system. In addition, LCZ696 could reduce the expression of hsCRP through reduction in the expression of STAT3, a sign also demonstrated in different clinical studies such as JUPITER and CANTOS, which have allowed a great reduction in morbidity and mortality, revolutionizing modern cardiology. The antiinflammatory and angio-repairing effect of LCZ696 is probably reflected in an improvement in the survival of patients who receive a treatment regimen with this drug in studies such as

could be counter-regulated by IL-1ß [26–28].

endothelial level. MAS1R could be counter-regulated by IL-1ß.

PARADIGM-HF [29–31].

The physiopathological mechanisms proposed in our work are summarized in **Figure 3**. The dual blocking of NEP/AT1R by LCZ696 could reduce the expression and phosphorylation of STAT3 through JAK, either by blocking AT1R, reducing oxidative stress, or controlling systolic blood pressure.

The reduction of STAT3 produced a decrease in the inflammatory transcription factors in the nucleus and a release of hsCRP in the blood circulation, which produces an increasing docking of the alpha subunit of IL-6R toward the membrane. Through this pathway, vascular remodeling and LVH were reduced because part of the growth factors and migration of muscle cells depend on the activation of the inflammatory cascade.

of the NPRA receptor. On the other hand, the blockade of AT1R can decrease fibrosis, induce vasodilation, reduce the retention of sodium and water, lower blood pressure, and other

The most important clinical study that demonstrated the reduction of cardiovascular morbidity and mortality in patients with heart failure was the PARADIGM-HF study, which showed a clear benefit in patients who were in the branch receiving LCZ696. However, studies in experimental animals and pathophysiological analyses are scarce. Thus, the precise mechanism by which LCZ696 reduces cardiovascular mortality remains unclear. Some authors have proposed different hypotheses: (1) a sustained increase in natriuretic peptides by inhibition of NEP, (2) a direct hemodynamic effect that reduces stress on the left ventricular wall, (3) a reduction in arrhythmias and by a reduction in fibrosis or myocardial hypertrophy, and (4)

Previously, drug-intervention studies in this model have shown that some antihypertensive treatments, with candesartan, telmisartan, and losartan, not only lower blood pressure but also cause an improvement in redox balance and regression of structural changes in resistance arteries, although not a regeneration of the endothelium. In other words, reversing adverse effects associated with hypertension does not improve the normal structure and function of

Within the inflammatory cascades activated in this experimental model, we found that the determinant of the previously evidenced changes is that of the IL-6 receptor. Two different forms of IL-6 cell receptors have been described: an 80 kDa ligand-binding chain, known as IL-6R (IL-6Ra, CD126), and a 130 kDa signal transduction chain, gp130 (IL-6Rb, CD130). Gp130 is present in many places and situations; in contrast, IL-6R shows a more limited expression

In a recent publication of our group, it can be concluded that LCZ696 can reverse the changes associated with vascular remodeling, even more important than just blocking AT1R. The proposed pathway to demonstrate this finding was through the inhibition of the intracellular cascade of STAT3/JAK in intimate relation with IL-6R alpha, thus demonstrating an intrinsic anti-inflammatory effect. In addition, from the inhibition of STAT3, LCZ696 managed to significantly increase the amount of EPC at the vascular level, thus mediating endothelial

The physiopathological mechanisms proposed in our work are summarized in **Figure 3**. The dual blocking of NEP/AT1R by LCZ696 could reduce the expression and phosphorylation of STAT3 through JAK, either by blocking AT1R, reducing oxidative stress, or controlling systolic

The reduction of STAT3 produced a decrease in the inflammatory transcription factors in the nucleus and a release of hsCRP in the blood circulation, which produces an increasing docking of the alpha subunit of IL-6R toward the membrane. Through this pathway, vascular remodeling and LVH were reduced because part of the growth factors and migration of

muscle cells depend on the activation of the inflammatory cascade.

an improvement of regional myocardial perfusion [4].

effects [23].

82 Ultimate Guide to Insulin

endothelial cells [8, 9].

pattern [24].

repair [25].

blood pressure.

**Figure 3.** The phytopathological mechanisms proposed in our work are summarized in this image. The dual blocking of NEP/AT1R by LCZ696 could reduce the expression and phosphorylation of STAT3 through JAK, either by blocking AT1R, reducing oxidative stress, or controlling systolic blood pressure. The reduction of STAT3 produced a decrease in the inflammatory transcription factors in the nucleus and a release of hsCRP in the blood circulation, which produces an increasing docking of the alpha subunit of IL-6R toward the membrane. On the other hand, NEP and ACE2 probably induce the conversion of angiotensin II in different intermediate metabolites, such as angiotensin 1-7 (Ang 1-7), which produces antagonistic effects to angiotensin II by MAS1R. The intracellular cascade of MAS1R, by MAPK/ERK, produces a fundamental effect, namely, the production of VEGF and its two receptors: VEGFR1 and 2. From this mechanism, the endothelium could be repaired and/or replaced, favoring the maturation of circulating EPCs on resident EPCs at the endothelial level. MAS1R could be counter-regulated by IL-1ß.

On the other hand, NEP and ACE2 probably induce the conversion of angiotensin II in different intermediate metabolites, such as angiotensin 1-7 (Ang 1-7), which produces antagonistic effects to angiotensin II by MAS1R. The intracellular cascade of MAS1R, by MAPK/ERK, produces a fundamental effect, namely, the production of VEGF and its two receptors, VEGFR1 and VEGFR2. From this mechanism, the endothelium could be repaired and/or replaced, favoring the maturation of circulating EPCs on resident EPCs at the endothelial level. MAS1R could be counter-regulated by IL-1ß [26–28].

In conclusion, we postulate that LCZ696, by MAS1R activation, is not only able to improve endothelial function but also able to repair the endothelium, and this probably allows for improved functionality of the entire cardiovascular system. In addition, LCZ696 could reduce the expression of hsCRP through reduction in the expression of STAT3, a sign also demonstrated in different clinical studies such as JUPITER and CANTOS, which have allowed a great reduction in morbidity and mortality, revolutionizing modern cardiology. The antiinflammatory and angio-repairing effect of LCZ696 is probably reflected in an improvement in the survival of patients who receive a treatment regimen with this drug in studies such as PARADIGM-HF [29–31].

#### **3.2. Gliptin on vascular inflammation**

Renna et al. suggest that incretin system dysfunction, as happens in patients with diabetes mellitus or metabolic syndrome, allows activation of inflammatory response in different levels. The consequence is the creation of a vascular microenvironment that is conducive to the creation, perpetuation, progression, and destabilization of vascular injury, with either a simple eutrophic mechanism of vascular remodeling or the generation of an atherosclerotic lesion [32].

microenvironment, preventing vascular modeling and the subsequent formation of atheromatous plaques. Another pharmacological group that has gained importance in recent years is LCZ696, which, as several clinical studies have shown, modifies the cardiovascular morbidity and mortality of one of the most frequent pathologies of clinical practice, heart failure. However, new studies show that it is capable of producing effects in vascular repair, increasing the CPE at the vascular level, and avoiding vascular remodeling, even in experimental models with insulin resistance.

The concept of remodeling and vascular inflammation, which a decade ago was only important at the level of basic research, step-by-step has proven crucial in the appearance of atherosclerosis, called subclinical atherosclerosis. Much progress has been made in the treatment and discovery of pathophysiological mechanisms, rest improve the studies of deterrence, and its correlation with the reduction of cardiovascular risk; this is, perhaps, the decade in which

1 Department of Pathology, School of Medicine, National University of Cuyo, Argentina 2 National Council of Scientific and Technical Research (IMBECU-CONICET), Argentina

[1] Shanthi M, Pekka P, Bo N. Global Atlas on Cardiovascular Disease Prevention and Control.

[2] Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: A report from the American Heart Association. Circulation.

[3] Kaplan N. The deadly quartet hyperbody obesity, glucose intolerance, hypertriglyceri-

[4] Reaven G, Laws A. Insulin resistance, compensatory hyperinsulinemia and coronary

demia, and hypertension. Archives of Internal Medicine. 1989;**149**:1514-1520

, Rodrigo Damián Garcia1,2 and

Role of Insulin Resistance in Vascular Inflammation http://dx.doi.org/10.5772/intechopen.77287 85

we can advance in this.

**Conflict of interest**

**Author details**

**References**

Roberto Miguel Miatello1,2

2017;**135**:e146-e603

The authors have no "conflict of interest" to declare.

Nicolás Federico Renna1,2\*, Jésica Magalí Ramirez3

\*Address all correspondence to: nicolasfede@gmail.com

Geneva: World Health Organization; 2011

heart disease. Diabetologia. 1994;**37**:948-952

3 Department of Cardiology, Spanish Hospital of Mendoza, Argentina

Several mechanisms may underlie these results: (1) increase the circulating levels of GLP-1 [33]. The cardiovascular actions of GLP-1 may occur either directly through the GLP-1 receptor or through a GLP-1 receptor-independent effect of the degradation product of GLP-1 [38]; (2) DPP-IV also degrades GIP and potentially cytokines and certain chemokines (including stromal-derived factor 1-α). Thus, other substrates of DPP-IV may be responsible for the improvement in endothelial function. Alternatively, DDP-IV inhibition might improve endothelial function by influencing insulin and glucose levels. Insulin causes vasodilation by increasing endothelial production of NO [34].

The improvement in endothelial function and oxidative stress could result in a decrease in activation of the inflammatory process.

Other authors have suggested that the DDP-IV inhibitors may have anti-inflammatory effects, such as reduced activation of TNF-alpha during macrophage activation [33, 35].
