Abstract
Mechanisms underlying hypertensive target organ damage (TOD) are not completely understood. The pathophysiological role of mitochondrial oxidative stress, resulting from mitochondrial dysfunction, in development of TOD is unclear. The stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable model of human hypertension and of its vascular consequences. Pathogenesis of TOD in SHRSP is multifactorial, being determined by high blood pressure levels, high salt/low potassium diet, and genetic factors. Accumulating evidence points to a key role of mitochondrial dysfunction in increased susceptibility to TOD development of SHRSP. Mitochondrial abnormalities were described in both heart and brain of SHRSP. Pharmacological compounds able to protect mitochondrial function exerted a significant protective effect on TOD development, independently of blood pressure levels. Through our research efforts, we discovered that two genes encoding mitochondrial proteins, one (Ndufc2) involved in OXPHOS complex I assembly and activity and the second one (UCP2) involved in clearance of mitochondrial ROS, are responsible, when dysregulated, for vascular damage in SHRSP. The suitability of SHRSP as a model of human disease represents a promising background for future translation of the experimental findings to human hypertension. Novel therapeutic strategies toward mitochondrial molecular targets may become a valuable tool for prevention and treatment of TOD in human hypertension.
Highlights
It has been clearly understood that the complexity of the etiopathogenetic basis of human hypertension extends to the etiopathogenesis of the related target organ damage (TOD) [1]
Predisposition to stroke is accelerated in the SHRSP by feeding with a high salt/low potassium dietary regimen (Japanese style diet) and it is preceded by renal damage occurrence [5, 6]
We will discuss the available evidence related to genes encoding mitochondrial proteins, underlying both stroke and renal damage development in SHRSP, that were discovered within STR1
Summary
It has been clearly understood that the complexity of the etiopathogenetic basis of human hypertension extends to the etiopathogenesis of the related TOD [1]. One-year follow-up of both strains maintained under regular dietary feeding revealed increased occurrence of renal, cerebrovascular, and cardiac damage in SHRSP as compared to the SHRSR in association with higher BP levels [4]. Histopathological studies of the brain reveal most of the key signs of small vessel disease: segmental wall damage, depletion of smooth myocytes, accumulation of fibrous tissue, wall thickening, luminal narrowing, blood brain barrier leakage, and perivascular oedema. These alterations can be summarized as a fibrinoid vascular lesion caused by a degenerative-infiltrative-proliferative disease process which affects short segments of penetrating arterioles in multiple, wide scattered foci [10, 11]
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