Jahresbericht der Klinik - Klinik für Kardiologie - UniversitätsSpital ...

Francesco Cosentino, MD, PhD
Research Group Leader & Visiting Prof.
Basic Cardiovascular Research
Diabetes Mellitus and the Vessel Wall
Patients with diabetes are at risk of cardiovascular diseases (CVD). It
was reported that p66 Shc protein is involved in modulation of oxidative
stress. Mice lacking p66 Shc (p66 Shc−/− ) have increased resistance
to reactive oxygen species (ROS) and prolonged life span. Although
the exact biochemical role of p66 Shc has yet to be determined, it participates
in mitochondrial ROS production. In response to stress signals,
p66 Shc is activated by PKC and enters the mitochondrion, where
it leads to accumulation of ROS and cellular death. We demonstrated
that p66 Shc activation is crucial for induction of diabetic vascular dysfunction.
Indeed, p66 Shc deletion prevents endothelial dysfunction
and oxidative stress in diabetic mice. p66 Shc−/− diabetic mice showed
lower ROS which accounted for the preserved NO release.
Recently, we focused on the molecular mechanisms underlying the
long-lasting effects of hyperglycemia despite optimal glucose control.
This investigation relies on clinical trials showing that intensive
glycemic control has failed to reduce the burden of cardiovascular
disease in diabetes. Of note, glucose-lowering therapy was started
after a duration of diabetes ranging from 8 to 11 years. By contrast,
early treatment of hyperglycemia reduces myocardial infarction and
mortality. These observations support the hypothesis that hyperglycemic
environment is remembered in the vasculature. ROS are likely
involved in this «memory» phenomenon but the signaling pathways
responsible for persistence of ROS production after glucose normalization
are unknown.
Hyperglycemia
Endothelial cell
Hyperglycemic
Memory
Normoglycemia
PKCβ₂
p66Shc NADPH
ROS
Since human and experimental diabetes have been associated with
upregulation of p66 Shc , we hypothesize that its activation may continue
despite glucose normalization, perpetuating redox vascular
damage. Our preliminary data show that restoration of normal glucose
levels does not affect p66 Shc upregulation, or ROS increase in
human endothelial cells [Fig. 1]. Furthermore, we targeted p66 Shc at
the time of glucose normalization. Its selective knockdown resulted
in less oxidative stress and apoptosis, suggesting p66 Shc plays a role
in hyperglycemic memory.
NO
Endothelial Dysfunction
Vascular Damage
Cardiovascular Events
Fig. 1 Schematic representation of p66Shc critical involvement
in vascular hyperglycemic memory
We have confirmed these findings in vivo showing that restoration of
normoglycemia by insulin does not revert p66 Shc activation in diabetic
mice. Our investigation will elucidate upstream signaling pathways
linking persistent hyperglycemic stress to ROS generation and, hence,
CVD. Thus, a better understanding of p66 Shc appears to be of utmost
importance and may provide a new therapeutic avenue to reduce
cardiovascular health burden.
Fig. 2 Francesco Cosentino (MD, PhD) and his research group
(left to right): Sarah Costantino (PhD student), Francesco
Cosentino (MD, PhD), Francesco Paneni (MD, PhD student)
and Elena Osto (MD, PhD)