Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease

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.

Figure 1

Schematic representation of the electron transport chain OXPHOS within the inner mitochondrial membrane. Complex I is highlighted to underscore its major relevance as a determinant of excessive mitochondrial ROS production when it becomes dysfunctional. In particular, lack of Ndufc2 subunit of complex I is highlighted to indicate that it leads to disassembly and dysfunction of the complex. As a result, NADH cannot be converted to NAD⁺, with consequent reduction of the flux of protons into the matrix, significant decrease of mitochondrial membrane potential, increase of anion superoxide, and reduction of ATP synthesis. The resulting cellular and tissue damage can contribute to target organ damage development in hypertension.

Figure 2

Schematic representation of the effects of UCP2 downregulation within the inner mitochondrial membrane. As a consequence of the reduced UCP2 function, a lower number of protons are shifted into the matrix with a consequent increase of reactive oxygen species and dysfunction of the whole OXPHOS with decreased ATP synthesis and cellular damage.