Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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endothelial cells from hypertensive subjects exhibit increased expression of induc-

ible NO synthase (iNOS), which is calcium independent and, consequently, pres-

ents a higher activity when compared to eNOS. Therefore, iNOS reacts with BH4

and reduces its bioavailability for eNOS, increasing its uncoupled state [ 99 ].

Similar to the effects observed in the brain, the presence of reactive oxygen spe-

cies, pro-inflammatory cytokines and activated tissue renin-angiotensin system

triggers a positive feedback mechanism in the vessel wall. Elevated reactive oxygen

species inactivate protein tyrosine phosphatases through irreversible catalytic

cysteine oxidation [ 100 , 101 ]. This post-translational modification increases MAPK

signaling pathway and the transcriptional activity of several factors [NF-kB, cAMP

response element-binding protein (CREB) and activator protein-1 (AP-1)] that

intensify gene expression of many pro-inflammatory cytokines, NADPH oxidase

subunits and several RAS components amplifying both endothelial dysfunction and

vascular remodeling.

In the smooth muscle cells of the arteriolar wall, Angiotensin II exerts direct

vasoconstrictor and trophic effects. In smooth muscle cells isolated from rat arter-

ies, angiotensin II modulates several types of ionic channels, activates protein kinase

C and inhibits protein kinase A [ 102 – 104 ]. These effects inhibit voltage-gated K+,

delayed rectifier K+ and ATP-sensitive K+ channels causing a subsequent vasocon-

striction, which increase vasomotor tonus and the total peripheral vascular resis-

tance [ 102 – 104 ].

In the conductance arteries, angiotensin II, via AT1 receptor signaling, also pro-

motes monocyte chemotactic protein-1 (MCP-1) and transforming growing

factor-β 1 (TGF-β1) gene expression in smooth muscle cells, which act autocrinally

through C-C chemokine receptor type 2 (CCR2) and type II TGFβ receptor (TβRII),

respectively. These molecular signaling pathways increase MCP-1, matrix metallo-

proteinase- 2 (MMP2), fibronectin and collagen [ 105 – 107 ]. Although collagen accu-

mulation is identified in adult hypertensive animals, it is not observed in

pre-hypertensive SHRs that already demonstrate increased arterial stiffness, exclud-

ing the causative role of collagen in arterial stiffness [ 97 , 98 ]. MMP2 cleaves the

latent TGF-β 1 form (TGF-β 1 associated with Latency Associated Protein) releasing

TGF-β 1 active form. MMP2 also cleaves pro-endothelin-1 to endothelin-1 active

form, which mimics angiotensin II’s molecular effects. Additionally to activating

peptides, MMP2 is able to digest elastin and, consequently, induces internal elastic

lamina fragmentation, all these effects contributing to increase arterial stiffness.

In hypertensive individuals, augmented arterial stiffness increases pulse wave

velocity, facilitating the return of reflective waves to left ventricle during the systole,

which increase the systolic pressure. Then, the myocardium has to increase ven-

tricular pressure to overcome the higher resistance to left ventricle ejection. As a

result, left ventricle hypertrophies [ 108 ], compromising its perfusion and leading to

myocardium ischemia especially during elevated metabolic demand, as the sub-

maximal exercise. Arterial stiffness-induced increased pulsatility also promotes

smooth muscle cells hypertrophy in arterioles and a further increase in total periph-

eral resistance and the consequent elevation of diastolic arterial pressure [ 108 ].

16 Experimental Evidences Supporting Training-Induced Benefits inflSpontaneously...